Method of treatment using phenyl and biaryl derivatives as prostaglandin E inhibitors and compounds useful therefore

ABSTRACT

This invention encompasses a method for the treatment or prevention of prostaglandin mediated diseases comprising administering to a mammalian patient a compound of formula I:in an amount that is effective to treat or prevent said prostaglandin mediated disease. Novel compounds are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/199,299, filed on Apr. 24, 2000.

BACKGROUND OF THE INVENTION

This invention relates to methods for treating prostaglandin mediateddiseases. More particularly, the compounds are antagonists of the painand inflammatory effects of E-type prostaglandins. Additionallypreferred compounds are included.

Two review articles describe the characterization and therapeuticrelevance of the prostanoid receptors as well as the most commonly usedselective agonists and antagonists: Eicosanoids: From Biotechnology toTherapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds,Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of LipidMediators and Cell Signalling, 1996, 14, 83-87. An article from TheBritish Journal of Pharmacology (1994, 112, 735-740) suggests thatProstaglandin E₂ (PGE₂) exerts allodynia through the EP₁ receptorsubtype and hyperalgesia through EP₂ and EP₃ receptors in the mousespinal cord.

Thus, selective prostaglandin ligands, agonists or antagonists,depending on which prostaglandin E receptor subtype is being considered,have anti-inflammatory, antipyretic and analgesic properties similar toa conventional non-steroidal anti-inflammatory drug, and in addition,inhibit hormone-induced uterine contractions and have anti-cancereffects. These compounds have a diminished ability to induce some of themechanism-based side effects of NSAIDs which are indiscriminatecyclooxygenase inhibitors. In particular, the compounds have a reducedpotential for gastrointestinal toxicity, a reduced potential for renalside effects, a reduced effect on bleeding times and a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.

In The American Physiological Society (1994, 267, R289-R-294), studiessuggest that PGE2-induced hyperthermia in the rat is mediatedpredominantly through the EP1 receptor. World patent applications WO96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1(Jan. 8, 1997) disclose compounds as being useful in the treatment ofprostaglandin mediated diseases.

SUMMARY OF THE INVENTION

A method of treating or preventing a prostaglandin E mediated disease isdescribed which comprises administering to a mammalian patient in needof such treatment or prevention a compound of formula I:

wherein:

R is a group Ar as defined hereinafter;

R¹ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, X(CH₂)_(p)Ar, or amethylenedioxy group attached to two adjacent ring carbon atoms;

R² is —(CH₂)_(x)C(O)N(R⁴)S(O)_(y)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)C(O)R⁵,—(CH₂)_(x)C(O)N(R⁴)C(O)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)S(O)_(y)R⁵,—(CH₂)_(x)CO₂R⁴, or tetrazol-5-yl optionally substituted by C₁₋₆alkyl;

R³ is X(CH₂)_(p)Ar or X(CH₂)_(p)R⁴ or a group of formula (a):

Ar is a group of formula (b) or (c):

 or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl,oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl,imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl,thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, orpyrimidinyl, all of which may be unsubstituted or substituted by one ormore R⁷ or R⁸ groups;

A is C═O or (C(R⁴)₂)_(m);

each B is independently —CH₂— or —O—;

R⁴ is hydrogen or C₁₋₆alkyl;

R⁵ is hydrogen or C₁₋₁₀alkyl or Ar, both of which may be unsubstitutedor substituted by one or two Cl, F, Br, hydroxy, XC₁₋₅alkyl, C₁₋₅alkyl,NO₂, tetrazol-5-yl optionally substituted by C₁₋₆alkyl, or R⁵ is N(R⁴)₂;

R⁶ is hydrogen, R¹⁰, CO₂R¹¹, CO₂C(R¹⁰)₂O(CO)XR¹¹, PO₃(R¹¹)₂, SO₂NR¹¹R¹⁰,NR¹¹SO₂R¹⁰, CONR¹¹SO₂R¹⁰, SO₃R¹¹, S(O)_(q)R¹¹, S(O)_(q)N(R¹¹)C(O)R¹⁰,S(O)_(q)N(R¹¹)S(O)_(q)R¹⁰, C(O)N(R¹¹)C(O)R¹⁰, N(R¹¹)C(O)R¹⁰, N(R¹¹)₂,N(R¹¹)C(O)NR¹¹, P(O)(OR¹¹)R¹¹, CN, —CO₂(CH₂)_(m)C(O)N(R⁴)₂,C(R¹⁰)₂N(R¹¹)₂, C(O)N(R⁴)₂, OR⁴ or tetrazolyl optionally substituted byC1-6 alkyl;

R⁷ and R⁹ are independently hydrogen, R¹⁰, OH, C₁₋₈ alkoxy, S(O)_(q)R¹⁰,N(R⁴) ₂, Br, F, I, Cl, CF₃, NO₂, NHCOR⁴, R¹²CO₂R¹¹, —X—R¹³—Y,—X(CR⁴)_(p)OR⁴, S(CH₂)_(p)CO₂H, (CH₂)_(p)X—R¹³, —X(CH₂)_(p)CONR¹¹SO₂R¹⁰,(CH₂)_(p)XCONR¹¹SO₂R¹⁰ or X(CH₂)_(p)R⁶ wherein each methylene groupwithin —X(CH₂)_(q)R⁶ may be unsubstituted or substituted by one or two—(CH₂)_(p)Ar groups;

R⁸ is hydrogen, R¹⁰, OH, C₁₋₅alkoxy, S(O)_(q)R¹⁰, N(R⁴)₂, Br, F, I, Clor NHCOR⁴ wherein the C₁₋₅ alkoxy may be unsubstituted or substituted byOH, methoxy or halogen;

R¹⁰ is hydrogen, Ar, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, all ofwhich may be unsubstituted or substituted by one or more OH,.CH₂OH,N(R⁴)₂ or halogen; or R¹⁰ is N(R⁴)₂;

R¹¹ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₈alkynyl,all of which may be unsubstituted or substituted by one or more OH,N(R⁴)₂, CO₂R¹⁴, halogen or XC₁₋₅alkyl; or R¹¹ is (CH₂)_(p)Ar;

R¹² is divalent Ar, C₁₋₁₀alkylene, C₁₋₁₀alkylidene, C₂₋₁₀alkenylene,C₂₋₁₀alkynylene, all of which may be unsubstituted or substituted by oneor more of OH, CH₂OH, N(R⁴)₂ or halogen;

R¹³ is a bond, C₁₋₁₀alkylene, C₁₋₁₀alkenylene, C₁₋₁₀alkylidene,C₁₋₁₀alkynylene, all of which may be linear or branched, or phenylene,all of which may be unsubstituted or substituted by one or more OH,N(R⁴)₂, COOH or halogen;

R¹⁴ is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₇alkynyl;

X is (CH₂)_(p),O, NR⁴ or S(O)_(p);

Y is CH₃ or X(CH₂)_(p)Ar;

q is zero, one or two;

p is an integer from 0 to 6;

m is 1, 2 or 3;

n is 1 to 4;

x is 0 to 4;

y is 1 or 2;

the dotted line signifies the optional presence of a bond such that itrepresents a single or double bond.

DETAILED DESCRIPTION

In one aspect of the invention, a method of treating or preventing aprostaglandin E mediated disease is described which comprisesadministering to a mammalian patient in need of such treatment orprevention a compound of formula I:

wherein:

R is a group Ar as defined hereinafter;

R¹ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, X(CH₂)_(p)Ar, or amethylenedioxy group attached to two adjacent ring carbon atoms;

R² is —(CH₂)_(x)C(O)N(R⁴)S(O)_(y)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)C(O)R⁵,—(CH₂)_(x)C(O)N(R⁴)C(O)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)S(O)_(y)R⁵,—(CH₂)_(x)CO₂R⁴, or tetrazol-5-yl optionally substituted by C₁₋₆alkyl;

R³ is X(CH₂)_(p)Ar or X(CH₂)_(p)R⁴ or a group of formula (a):

Ar is a group of formula (b) or (c):

 or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl,oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl,imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl,thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, orpyrimidinyl, all of which may be unsubstituted or substituted by one ormore R⁷ or R⁸ groups;

A is C═O or (C(R⁴)₂)_(m);

each B is independently —CH₂— or —O—;

R⁴ is hydrogen or C₁₋₆alkyl;

R⁵ is hydrogen or C₁₋₁₀alkyl or Ar, both of which may be unsubstitutedor substituted by one or two Cl, F, Br, hydroxy, XC₁₋₅alkyl, C₁₋₅alkyl,NO₂, tetrazol-5-yl optionally substituted by C₁₋₆alkyl, or R⁵ is N(R⁴)₂;

R⁶ is hydrogen, R¹⁰, CO₂R¹¹, CO₂C(R¹⁰)₂O(CO)XR¹¹, PO₃(R¹¹)₂, SO₂NR¹¹R¹⁰,NR¹¹SO₂R¹⁰, CONR¹¹SO₂R¹⁰, SO₃R¹¹, S(O)_(q)R¹¹, S(O)_(q)N(R¹¹)C(O)R¹⁰,S(O)_(q)N(R¹¹)S(O)_(q)R¹⁰, C(O)N(R¹¹)C(O)R¹⁰, N(R¹¹)C(O)R¹⁰, N(R¹¹)₂,N(R¹¹)C(O)NR¹¹, P(O)(OR¹¹)R¹¹, CN, —CO₂(CH₂)_(m)C(O)N(R⁴)₂,C(R¹⁰)₂N(R¹¹)₂, C(O)N(R⁴)₂, OR⁴ or tetrazolyl optionally substituted byC1-6 alkyl;

R⁷ and R⁹ are independently hydrogen, R¹⁰, OH, C₁₋₈ alkoxy, S(O)_(q)R¹⁰,N(R⁴)₂, Br, F, I, Cl, CF₃, NO₂, NHCOR⁴, R¹²CO₂R¹¹, —X—R¹³—Y,—X(CR⁴)_(p)OR⁴, S(CH₂)_(p)CO₂H, (CH₂)_(p)X—R¹³, —X(CH₂)_(p)CONR¹¹SO₂R¹⁰,(CH₂)_(p)XCONR¹¹SO₂R¹⁰ or X(CH₂)_(p)R⁶ wherein each methylene groupwithin —X(CH₂)_(q)R⁶ may be unsubstituted or substituted by one or two—(CH₂)_(p)Ar groups;

R⁸ is hydrogen, R¹⁰, OH, C₁₋₅alkoxy, S(O)_(q)R¹⁰, N(R⁴)₂, Br, F, I, Clor NHCOR⁴ wherein the C₁₋₅ alkoxy may be unsubstituted or substituted byOH, methoxy or halogen;

R¹⁰ is hydrogen, Ar, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, all ofwhich may be unsubstituted or substituted by one or more OH,.CH₂OH,N(R⁴)₂ or halogen; or R¹⁰ is N(R⁴)₂;

R¹¹ is independently hydrogen, C₁₋₁₀alkyl, C₂₋₁alkenyl or C₂₋₈alkynyl,all of which may be unsubstituted or substituted by one or more OH,N(R⁴)₂, CO₂R¹⁴, halogen or XC₁₋₅alkyl; or R¹¹ is (CH₂)_(p)Ar;

R¹² is divalent Ar, C₁₋₁₀alkylene, C₁₋₁₀alkylidene, C₂₋₁₀alkenylene,C₂₋₁₀alkynylene, all of which may be unsubstituted or substituted by oneor more of OH, CH₂OH, N(R⁴)₂ or halogen;

R¹³ is a bond, C₁₋₁₀alkylene, C₁₋₁₀alkenylene, C₁₋₁₀alkylidene,C₁₋₁₀alkynylene, all of which may be linear or branched, or phenylene,all of which may be unsubstituted or substituted by one or more OH,N(R⁴)₂, COOH or halogen;

R¹⁴ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₇ alkynyl;

X is (CH₂)_(p), O, NR⁴ or S(O)_(p);

Y is CH₃ or X(CH₂)_(p)Ar;

q is zero, one or two;

p is an integer from 0 to 6;

m is 1, 2 or 3;

n is 1 to 4;

x is 0 to 4;

y is 1 or 2;

the dotted line signifies the optional presence of a bond such that itrepresents a single or double bond.

An embodiment of the invention that is of particular interest relates toa method of treating or preventing a prostaglandin mediated diseasecomprising administering to a mammalian patient in need of suchtreatment a compound of formula I in an amount which is effective fortreating or preventing a prostaglandin mediated disease, wherein theprostaglandin mediated disease is selected from the group consisting of:

(1) pain, fever or inflammation associated with rheumatic fever,influenza or other viral infections, common cold, low back and neckpain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, bursitis, burnsincluding radiation and corrosive chemical injuries, sunburns, painfollowing surgical and dental procedures as well as immune andautoimmune diseases;

(2) cellular neoplastic transformations or metastic tumor growth;

(3) diabetic retinopathy and tumor angiogenesis;

(4) prostanoid-induced smooth muscle contraction associated withdysmenorrhea, premature labor, asthma or eosinophil related disorders;

(5) Alzheimer's disease;

(6) glaucoma;

(7) bone loss;

(8) osteoporosis;

(9) promotion of bone formation;

(10) Paget's disease;

(11) cytoprotection in peptic ulcers, gastritis, regional enteritis,ulcerative colitis, diverticulitis or other gastrointestinal lesions;

(12) GI bleeding and patients undergoing chemotherapy;

(13) coagulation disorders selected from hypoprothrombinemia,haemophilia and other bleeding problems;

(14) kidney disease;

(15) thrombosis;

(16) occlusive vascular disease;

(17) presurgery; and

(18) anti-coagulation.

Another embodiment of the invention is a method of treating orpreventing prostaglandin mediated disease comprising administering to amammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the prostaglandin mediated disease is selectedfrom the group consisting of: pain, fever or inflammation associatedwith rheumatic fever, influenza or other viral infections, common cold,low back and neck pain, skeletal pain, postpartum pain, dysmenorrhea,headache, migraine, toothache, sprains and strains, myositis, neuralgia,synovitis, arthritis, including rheumatoid arthritis, degenerative jointdiseases (osteoarthritis), gout and ankylosing spondylitis, bursitis,burns including radiation and corrosive chemical injuries, sunburns,pain following surgical and dental procedures as well as immune andautoimmune diseases.

Another embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the prostaglandin mediated disease is pain,fever or inflammation associated with dysmenorrhea.

Another embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the compound is co-administered with otheragents or ingredients.

Another embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the compound is co-administered with anotheragent or ingredient selected from the group consisting of:

(1) an analgesic selected from acetaminophen, phenacetin, aspirin, anarcotic;

(2) a cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug ora conventional nonsteroidal anti-inflammatory drug;

(3) caffeine;

(4) an H₂-antagonist;

(5) aluminum or magnesium hydroxide;

(6) simethicone;

(7) a decongestant selected from phenylephrine, phenylpropanolamine,pseudophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxyephedrine;

(8) an antiitussive selected from codeine, hydrocodone, caramiphen,carbetapentane and dextramethorphan;

(9) another prostaglandin ligand selected from misoprostol, enprostil,rioprostil, omoprostol and rosaprostol; a diuretic; and

(10) a sedating or non-sedating antihistamine. Examples of COX-2inhibitors are disclosed in U.S. Pat. Nos. 5,474,995; 5,633,272; and5,466,823; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691,and WO 95/0051.

Another embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the compound is co-administered with acyclooxygenase-2 selective nonsteroidal anti-inflammatory drug or aconventional nonsteroidal anti-inflammatory drug.

Another embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the compound is co-administered with aconventional nonsteroidal anti-inflammatory drug selected from the groupconsisting of: aspirin, ibuprofen, naproxen, and ketoprofen.

Another embodiment of the invention is a method of treating orpreventing a prostaglandin mediated disease comprising administering toa mammalian patient in need of such treatment a compound of formula I inan amount which is effective for treating or preventing a prostaglandinmediated disease, wherein the compound is co-administered with acyclooxygenase-2 selective nonsteroidal anti-inflammatory drug selectedfrom rofecoxib and celecoxib.

Preferred subsets of compounds and species that are useful for themethods described herein are set forth in WO96/30358, incorporated byreference.

Additional preferred species for use in treating prostaglandin mediateddiseases or conditions include the following:

TABLE 1

R¹ R² R³ X Y(R^(7,8)) Z(R^(7,8)) A Cpd 2-(2,6-Cl₂- H H benzene 1,3benzene 1,2 benzene CH₂—CH₂ 1 benzyloxy) diyl diyl diyl 2-Benzyl H Hbenzene 1,3 benzene 1,2 benzene CH₂— oxy diyl diyl diyl CH(CH₃) 2-BenzylH H benzene 2,5-thiophene 1,2 benzene CH₂—CH₂ 3 oxy diyl diyl diyl2-Benzyl H H benzene 4,2-thiophene 1,2 benzene CH₂—CH₂ 4 oxy diyl diyldiyl 2-Benzyl 5-Cl H 3-pyridine 1,3 benzene 1,2 benzene CH₂—CH₂ 5 oxytriyl diyl diyl 2-Benzyl H H benzene 2,4-thiophene 1,2 benzene CH₂—CH₂ 6oxy diyl triyl (5-Cl) diyl 2-Benzyl H H benzene 1,3 benzene 1,2 benzeneCH═CH 7 oxy diyl diyl diyl 2-Benzyl H H benzene 3,5-pyridine 1,2 benzeneCH═CH 8 oxy diyl diyl diyl 2-(2,6-Cl₂- H H benzene 2,4-thiophene 1,2benzene CH₂—CH₂ 9 benzyloxy) diyl diyl diyl 2-Benzyl H H benzene4,2-thiophene 1,2 benzene CH₂— 10 oxy diyl diyl diyl CH(CH₃) H H Hnaphthyl 1,3 benzene 1,2 benzene CH₂—CH₂ 11 diyl diyl H H H phenyl 1,3benzene 1,2 benzene CH₂—CH₂ 12 diyl diyl 2-Benzyl H H benzene 1,3benzene 1,2 benzene CH₂—CH₂— 13 oxy diyl diyl diyl CH₂ 2-Chloro 3-Cl Hbenzene 1,3 benzene 1,2 benzene CH₂—CH₂ 14 triyl diyl diyl 2-Benzyl H Hbenzene 2,4-thiophene 1,2 benzene CH₂—CH₂ 15 oxy diyl diyl diyl2-Phenoxy H H benzene 1,3 benzene 1,2 benzene CH₂—CH₂ 16 methyl diyldiyl diyl 4-Benzyl H H benzene 1,3 benzene 1,2 benzene CH₂—CH₂ 17 oxydiyl diyl diyl 4-Benzyl H H 1-naphtha 1,3 benzene 1,2 benzene CH₂—CH₂ 18oxy lenediyl diyl diyl 2-Benzyl H H benzene 2,5-thiophene 1,2 benzeneCH═CH 19 oxy diyl diyl diyl 2-Benzyl H H benzene 2,4-thiophene 1,2benzene CH═CH 20 oxy diyl diyl diyl 2-Benzyl H H benzene 1,3 benzene 1,2benzene CH₂—CH₂ 21 oxy diyl diyl diyl 2-Benzyl 4-F 5-F benzene3,5-thiophene 1,2 benzene CH₂—CH₂ 22 oxy tetrayl diyl diyl 2-Benzyl 3-F5-F benzene 3,5-thiophene 1,2 benzene CH═CH 23 oxy tetrayl diyl diyl4-Benzyl H H benzene 3,5-thiophene 1,2 benzene CH═C(CH₃) 24 oxy diyldiyl diyl 4-Benzyl 3- H benzene 1,4-imidazole 1,2 benzene CH₂—CH₂ 25 oxyOMe triyl diyl diyl 2-Benzyl H H benzene 2,4-thiazole 1,2 benzene CH═CH26 oxy diyl diyl diyl 2-(4-MeO- H H benzene 2,5-thiazole 1,2 benzeneCH═C(CH₃) 27 benzyloxy) diyl diyl diyl 2-(4-CF₃- H H benzene4,2-thiazole 1,2 benzene CH₂—CH₂ 28 benzyloxy) diyl diyl diyl 2-(4-F- HH benzene 5,2-thiazole 1,2 benzene CH═CH 29 benzyloxy) diyl diyl diyl2-Benzyl H H benzene 2,4-oxazole 1,2 beuzene CH═C(CH₃) 30 oxy diyl diyldiyl 2-(4-MeO- H H benzene 2,5-oxazole 1,2 benzene CH₂—CH₂ 31 benzyloxy)diyl diyl diyl 2-(4-CF₃- H H benzene 4,2-oxazole 1,2 benzene CH═CH 32benzyloxy) diyl diyl diyl 2-(4-F- H H benzene 5,2-oxazole 1,2 benzeneCH═C(CH₃) 33 benzyloxy) diyl diyl diyl 2-Benzyl H H benzene2,4-pyrimidine 1,2 benzene CH₂—CH₂ 34 oxy diyl diyl diyl 2-(4-MeO- H Hbenzene 4,6-pyrimidine 1,2 benzene CH═CH 35 benzyloxy) diyl diyl diyl2-(4-CF₃- H H benzene 4,2-pyrimidine 1,2 benzene CH═C(CH₃) 36 benzyloxy)diyl diyl diyl 2-(4-F- H H benzene 6,4-pyrimidine 1,2 benzene CH₂—CH₂ 37benzyloxy) diyl diyl diyl 2-Benzyl H H benzene 2,6-pyridine 1,2 benzeneCH═CH 38 oxy diyl diyl diyl N-benzyl H H 3-indole 1,3-benzene 1,2benzene CH═C(CH₃) 39 diyl diyl triyl (3-Cl) N-benzyl H H 7-indole1,3-benzene 1,2 benzene CH₂—CH₂ 40 diyl diyl triyl (3-OMe) 2-Benzyl H Hbenzene 1,3-benzene 1,2 benzene CH═CH 41 oxy diyl triyl (5-Cl) triyl(4-F) 2-Benzyl H H benzene 1,3-benzene 1,2 benzene CH═C(CH₃) 42 oxy diyltriyl (5-OCF₃) triyl (4-Cl) 2-Benzyl H H benzene 1,3-benzene 1,2 benzeneCH₂—CH₂ 43 oxy diyl triyl (5-CN) triyl (5-Cl) 2-Benzyl H H benzene1,3-benzene 1,2 benzene CH═CH 44 oxy diyl triyl (5-Me) triyl (5-OMe)2-Benzyl H H benzene 1,3-benzene 1,2 benzene CH═C(CH₃) 45 oxy diyl triyl(2-Me) triyl (6-Cl) 2-Benzyl H H benzene 1,3-benzene 1,2 benzene CH₂—CH₂46 oxy diyl triyl (2-OMe) triyl (6-OMe) 3-Benzyl H H 2-pyridine1,3-benzene 1,2 benzene CH═CH 47 oxy diyl diyl diyl 3-Benzyl 5- H4-isothiazole 1,3-benzene 1,2 benzene CH═C(CH₃) 48 oxy Me triyl diyldiyl 4-Benzyl H H 5-pyrimide 1,3-benzene 1,2 benzene CH₂—CH₂ 49 oxy diyldiyl diyl 2-Benzyl H H 3-quinoline 1,3-benzene 1,2 benzene CH═CH 50 oxydiyl diyl diyl 4-Benzyl H H 3-quinoline 1,3-benzene 1,2 benzeneCH═C(CH₃) 51 oxy diyl diyl diyl 2-Benzyl H H benzene 1,4-imidazole 1,2benzene CH₂—CH₂ 52 oxy diyl diyl diyl

TABLE 2

R², R³ = H, Z = 1,2-benzenediyl R¹ X Y A R⁵ Cpd 2-Benzyloxy benzene 1,3benzene CH═CH 2-thienyl 53 diyl diyl 2-Benzyloxy benzene 1,3-benzeneCH₂—C(CH₃)₂ styryl 54 diyl diyl 2-(4-MeO- benzene 3,5-thiopheneCH₂—CH(CH₃) benzyl 55 benzyloxy) diyl diyl 2-(2,3-Cl₂- benzene1,3-benzene CH═CH cyclohexyl 56 benzyloxy) diyl diyl 2-Benzyloxy benzene3,5-thiophene CH₂—C(CH₃)₂ cyclopentyl 57 diyl diyl 2-(4-CF₃- benzene1,3-benzene CH₂—CH(CH₃) 4-Cl-phenyl 58 benzyloxy) diyl diyl 2-(2,3-Cl₂-benzene 3,5-thiophene CH═CH 4-MeO-phenyl 59 benzyloxy) diyl diyl2-(4-MeO- benzene 1,3-benzene CH₂—C(CH₃)₂ 4-(CH₃SO₂)phenyl 60 benzyloxy)diyl diyl 2-(4-CF₃- benzene 3,5-thiophene CH₂—CH(CH₃) 2-methylphenyl 61benzyloxy) diyl diyl 2-Benzyloxy benzene 1,3-benzene CH═CH2-MeO-5-Br-phenyl 62 diyl diyl 2-(4-MeO- benzene 3,5-thiopheneCH₂—C(CH₃)₂ 2,5-(CH₃)₂-phenyl 63 benzyloxy) diyl diyl 2-(2,3-Cl₂-benzene 1,3-benzene CH₂—CH(CH₃) 3,4-Cl₂-phenyl 64 benzyloxy) diyl diyl2-Benzyloxy benzene 3,5-thiophene CH═CH 3,5-Br₂-phenyl 65 diyl diyl2-(4-CF₃- benzene 1,3-benzene CH₂—C(CH₃)₂ 3-Cl-4-F-phenyl 66 benzyloxy)diyl diyl 2-(2,3-Cl₂- benzene 3,5-thiophene CH₂—CH(CH₃) 2-thiazoyl 67benzyloxy) diyl diyl 2-(4-MeO- benzene 1,3-benzene CH═CH 1-imidazoyl 68benzyloxy) diyl diyl 2-(4-CF₃- benzene 3,5-thiophene CH₂—C(CH₃)₂2-furanyl 69 benzyloxy) diyl diyl 2-Benzyloxy benzene 1,3-benzeneCH₂—CH(CH₃) 3-indolyl 70 diyl diyl 2-(4-CF₃- benzene 3,5-thiophene CH═CH2-quinolinyl 71 benzyloxy) diyl diyl

Representative compounds having a sulfonamide group are shown below.

TABLE 3

R¹ R² X Y(R^(7,8)) A B Cpd 3-(2-Ph—Et—SCH₂) H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 72 diyl diyl 4-(2-Ph—Et—SCH₂) H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 73 diyl diyl 4-(2-Ph—Et—SCH₂) H benzene 1,2 benzeneCH₂—CH₂—CH₂ 2-thienyl 74 diyl diyl 4-(3(-3-(2-Ph—Et— H benzene 1,2benzene CH₂—CH₂ 2-thienyl 75 SCH₂)Ph-oxy)Pr- diyl diyl oxy)4-(3(-3-(2-Ph—Et— H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 76S(O)—CH₂)Ph- diyl diyl oxy)Pr-oxy) 4-(3-(3-Me—Ph- H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 77 oxy)Pr-oxy) diyl diyl 4-(3(-3-(2-Ph—Et— H benzene1,2 benzene CH₂—CH₂ 2-thienyl 78 S(O)₂—CH₂)Ph- diyl diyl oxy)Pr-oxy)4-Carbazole-yl- H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 79 CH₂ diyl diyl4-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 80 diyl triyl(5-Bn) 4-(3-(3-Me—Ph- H benzene 1,2 benzene CH₂—CH(CH₃) 2-thienyl 81oxy)Pr-oxy) diyl diyl 4-(3-(3-(3-Ph)Pr- H benzene 1,2 benzene CH₂—CH₂2-thienyl 82 oxy CH₂)Ph- diyl diyl oxy)Pr-oxy) 4-(3-(2- H benzene 1,2benzene CH₂—CH₂ 2-thienyl 83 (Qn)ethenyl) diyl diyl Ph-oxy)Pr-oxy)4-(3-(3-2-((4-Cl- H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 84Ph)—Et)Ph-oxy)Pr- diyl diyl oxy) 4-(3-(3-(4-Ph—Ph- H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 85 oxy-CH₂)Ph- diyl diyl oxy)Pr-oxy) 3-(3-(3-Me—Ph- Hbenzene 1,2 benzene CH₂—CH₂ 2-thienyl 86 oxy)Pr-oxy) diyl diyl4-(2-(3-Tolyl) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 87 acetoxy CH₂)diyl diyl 4-(2-(3-Tolyl) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 88acetamide CH₂) diyl diyl 3-(3-(2-(Qn) CH₂ H benzene 1,2 benzene CH₂—CH₂2-thienyl 89 oxy) diyl diyl 3-Thiomethyl H benzene 1,2 benzene CH₂—CH₂2-thienyl 90 diyl diyl 3-Methylsulfone H benzene 1,2 benzene CH₂—CH₂2-thienyl 91 diyl diyl 4-(3-(3-Me—Ph- 3,5- benzene 1,2 benzene CH₂—CH₂2-thienyl 92 oxy)Pr-oxy) Br tetrayl diyl 3-(3-(2-(Qn) H benzene 1,2benzene CH₂—CH₂ 2-thienyl 93 ethenyl)Ph- diyl diyl oxy)Pr-oxy)3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 94 diyl diyl3-(3-(3-Me—Ph- H benzene 1,2 benzene CH₂— 2-thienyl 95 oxy)Pr-oxy) diyldiyl CH((CH₂)₃Ph) 3-(2-Ph-2-oxy- H benzene 1,2 benzene CH₂—CH₂ 2-thienyl96 ethoxy) diyl diyl 3-(2-(3-Phenyl-Pr- H benzene 1,2 benzene CH₂—CH₂2-thienyl 97 oxy)2-Ph-ethoxy) diyl diyl 3-(2-(Qn)ethenyl) H benzene 1,2benzene CH═CH 2-thienyl 98 diyl diyl 4-Chioro 3-Cl benzene 1,2 benzeneCH═CH 2-thienyl 99 triyl diyl 3-(2-(Qn)ethenyl) H benzene 1,2 benzeneCH═CH 2-thienyl 100 diyl triyl (5-CF₃) 3-(3-(3-Me—Ph- H benzene 1,2benzene CH═CH 2-MeO-5-Br- 101 oxy)Pr-oxy) diyl triyl (5-OMe) phenyl4-Chloro 3-Cl benzene 1,2 benzene CH═CH 3-Cl-4-F- 102 triyl triyl (5-Me)phenyl 3-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH═CH 2-thienyl 103 diyltriyl (5-Bn) 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 2-MeO-5-Br—104 diyl triyl (6-Cl) Ph 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH3-Cl-4-F- 105 oxy)Pr-oxy) diyl triyl (6-OMe) phenyl 4-Chloro 3-Clbenzene 1,2 benzene CH═CH 2-thienyl 106 triyl triyl (3-Cl)3-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH═CH 2-MeO-5-Br- 107 diyl triyl(3-OMe) Ph 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 3-Cl-4-F- 108diyl triyl (4-F) phenyl 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH2-thienyl 109 oxy)Pr-oxy) diyl triyl (4-Cl) 4-Chloro 3-Cl benzene 1,2benzene CH═CH 4-MeO- 110 triyl diyl phenyl 3-Ph—Et—SCH₂ H benzene 1,2benzene CH═CH 4-CF₃-phenyl 111 diyl diyl 3-(2-(Qn)ethenyl) H benzene 1,2benzene CH═CH 4-(CH₃SO₂) 112 diyl diyl phenyl 3-(3-(3-Me—Ph- H benzene1,2 benzene CH═CH 2-methyl 113 oxy)Pr-oxy) diyl diyl phenyl 4-Chloro3-Cl benzene 1,2 benzene CH═CH 2,3-Cl₂- 114 triyl diyl phenyl3-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH═CH 2-NO₂-4-Cl- 115 diyl diylphenyl 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 2,5-(CH₃)₂- 116diyl diyl phenyl 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH 2,6-F₂- 117oxy)Pr-oxy) diyl diyl phenyl 4-Chloro H benzene 1,2 benzene CH═CH3,4-Cl₂- 118 diyl diyl phenyl 3-(2-Ph—Et— SCH₂) H benzene 1,2 benzeneCH═CH 3,5-Br₂- 119 diyl diyl phenyl 3-(2-(Qn)ethenyl) H benzene 1,2benzene CH═CH 2-thiazoyl 120 diyl diyl 4-Bn H 2-thiophene 1,2 benzeneCH═CH 4-oxazoyl 121 diyl diyl 2-(4-MeO-benzyl) H 4-thiophene 1,2 benzeneCH═CH 1-imidazoyl 122 diyl diyl 4-(2,3-Cl₂-benzyl) H 1-imidazole 1,2benzene CH═CH 2-furanyl 123 diyl diyl 1-(4-CF₃-benzyl) H 4-imidazole 1,2benzene CH═CH 2-pyridinyl 124 diyl diyl 4-(4-F-benzyl) H 2-thiazole 1,2benzene CH═CH 3-indolyl 125 diyl diyl 5-Bn H 2-thiazole 1,2 benzeneCH═CH 2-quinolinyl 126 diyl diyl 2-(4-MeO-benzyl) H 4-thiazole 1,2benzene CH═CH 2-thienyl 127 diyl diyl 2-(2,3-Cl₂-benzyl) H 5-thiazole1,2 benzene CH═CH 2-thienyl 128 diyl diyl 4-(4-CF₃-benzyl) H 2-oxazole1,2 benzene CH═CH 2-thienyl 129 diyl diyl 5-(4-F-benzyl) H 2-oxazole 1,2benzene CH═CH 2-thienyl 130 diyl diyl 2-(2-Ph—Et— SCH₂) H 4-oxazole 1,2benzene CH═CH 2-thienyl 131 diyl diyl 2-Bn H 5-oxazole 1,2 benzene CH═CH2-thienyl 132 diyl diyl 4-(4-MeO-benzyl) H 2-pyrimidine 1,2 benzeneCH═CH 2-thienyl 133 diyl diyl 5-(2,3-Cl₂-benzyl) H 2-pyrimidine 1,2benzene CH═CH 2-thienyl 134 diyl diyl 6-(4-CF₃-benzyl) H 2-pyrimidine1,2 benzene CH═CH 2-thienyl 135 diyl diyl 2-(4-F-benzyl) H 4-pyrimidine1,2 benzene CH═CH 2-thienyl 136 diyl diyl 2-(2-Ph—Et— SCH₂) H 6-pyridine1,2 benzene CH═CH 2-thienyl 137 diyl diyl 6-Bn H 4-pyrimidine 1,2benzene CH═CH 2-thienyl 138 diyl diyl 4-(4-MeO-benzyl) H 6-pyrimidine1,2 benzene CH═CH 2-thienyl 139 diyl diyl N—Bn H 3-indole 1,2 benzeneCH═CH 2-thienyl 140 diyl diyl N—Bn H 7-indole 1,2 benzene CH═CH2-thienyl 141 diyl diyl 2-Benzyloxy H 6-pyridine 1,2 benzene CH═CH2-thienyl 142 diyl diyl Qn = 7-chloro-quinol-2-yl 2-Ph—Et—SMe =2-phenylethylthiomethyl 3-(3-Me—Ph-oxy)Pr-oxy =3-(3-methylphenoxy)propyl-1-oxy

Definitions

The following abbreviations have the indicated meanings:

Ac=acetyl

AIBN=2,2′-azobisisobutyronitrile

Bn=benzyl

DIBAL=diisobutyl aluminum hydride

DIPHOS=1,2-bis(diphenylphosphino)ethane

DMAP=4-(dimethylamino)pyridine

DMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxide

EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Et₃N=triethylamine

EtOAc=ethyl acetate

HBBS=Hanks balanced salt solution

HEPES=N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]

Hex=hexanes

KHMDS=potassium hexamethyldisilazane

LDA=lithium diisopropylamide

LPS=lipopolysaccharide

m-CPBA=metachloroperbenzoic acid

MES=2-[N-morpholino]ethanesulfonic acid

Ms=methanesulfonyl=mesyl

MsO=methanesulfonate=mesylate

NBS=N-bromosuccinimide

NSAID=non-steroidal anti-inflammatory drug

PCC=pyridinium chlorochromate

PDC=pyridinium dichromate

Ph=phenyl

PPTS=pyridinium p-toluenesulfonate

pTSA=p-toluenesulfonic acid

r.t.=room temperature

rac.=racemic

TLC=thin layer chromatography

Tf=trifluoromethanesulfonyl=triflyl

TfO=trifluoromethanesulfonate=triflate

THF=tetrahydrofuran

TLC=thin layer chromatography

Ts=p-toluenesulfonyl=tosyl

TsO=p-toluenesulfonate=tosylate

C₃H₅=allyl

Alkyl Group Abbreviations

Me=methyl

Et=ethyl

n-Pr=normal propyl

i-Pr=isopropyl

n-Bu=normal butyl

i-Bu=isobutyl

s-Bu=secondary butyl

t-Bu=tertiary butyl

c-Pr=cyclopropyl

c-Bu=cyclobutyl

c-Pen=cyclopentyl

c-Hex=cyclohexyl

The terms alkyl, alkenyl, and alkynyl mean linear, branched, and cyclicstructures and combinations thereof.

The term “alkyl” includes “cycloalkyl” and “lower alkyl” and extends tocover carbon fragments having up to 20 carbon atoms. Examples of alkylgroups include octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, and thelike.

“Lower alkyl” includes “lower cycloalkyl” and means alkyl groups of from1 to 7 carbon atoms. Examples of lower alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl,and the like.

“Cycloalkyl” includes “lower cycloalkyl” and means a hydrocarbon,containing one or more rings of from 3 to 12 carbon atoms, with thehydrocarbon having up to a total of 20 carbon atoms. Examples ofcycloalkyl groups are cyclopropyl, cyclopentyl, cyclo-heptyl,aldamantyl, cyclododecylmethyl, ₂-ethyl-1-bicyclo [4.4.0]decyl, and thelike.

“Lower cycloalkyl” means a hydrocarbon containing one or more rings offrom 3 to 7 carbon atoms, with the hydrocarbon having up to a total of 7carbon atoms. Examples of lower cycloalkyl groups are cyclopropyl,cyclopropylmethyl, cyclobutyl, 2-cyclopentylethyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl, and the like.

The term “alkenyl” includes “cycloalkenyl” and “lower alkenyl” and meansalkenyl groups of 2 to 20 carbon atoms. Examples of alkenyl groupsinclude allyl, 5-decen-1-yl, 2-dodecen-1-yl, and the like.

“Lower alkenyl” includes “lower cycloalkenyl” and means alkenyl groupsof 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Cycloalkenyl” includes “lower cycloalkenyl” and means alkenyl groups of3 to 20 carbon atoms, which include a ring of 3 to 12 carbon atoms, andin which the alkenyl double bond may be located anywhere in thestructure. Examples of cycloalkenyl groups are cyclopropen-1-yl,cyclohexen-3-yl, 2-vinyladamant-1-yl, 5-methylene-dodec-1-yl, and thelike.

“Lower cycloalkenyl” means alkenyl groups of 3 to 7 carbon atoms, whichinclude a ring of 3 to 7 carbon atoms and in which the double bond maybe located anywhere in the structure. Examples of lower cycloalkenylgroups are cyclopropen-1-yl, cyclohexen-3-yl, 2-cyclopentylethen-1-yl,and the like.

The term “alkynyl” includes “cycloalkynyl” and “lower alkynyl” and meansalkynyl groups of 2 to 20 carbon atoms. Examples of alkynyl groups areethynyl, 2-pentadecyn-1-yl, 1-eicosyn-1-yl, and the like.

“Lower alkynyl” includes “lower cycloalkynyl” and means alkynyl groupsof 2 to 7 carbon atoms. Examples of lower alkynyl groups includeethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkynyl” includes “lower cycloalkynyl” and means alkynyl groups of5 to 20 carbon atoms, which include a ring of 3 to 20 carbon atoms. Thealkynyl triple bond may be located anywhere in the group, with theproviso that if it is within a ring, such a ring must be of 10 membersor greater. Examples of cycloalkynyl are cyclododecyn-3-yl,3-cyclohexyl-1-propyn-1-yl, and the like.

“Lower cycloalkynyl” means alkynyl groups of 5 to 7 carbon atoms whichinclude a ring of 3 to 5 carbon atoms. Examples of lower cycloalkynylare cyclopropylethynyl, 3-(cyclobutyl)-1-propynyl, and the like.

Halogen includes F, Cl, Br, and I.

It is intended that the definition of any substituent in a particularmolecule be independent of its definition elsewhere in the molecule.

Optical Isomers—Diastereomers—Geometric Isomers

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Salts

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromnic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature and the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to avariety of factors including the age, weight, general health, sex, diet,time of administration, rate of excretion, drug combination and responseof the individual patient. In general, the daily dose from about 0.001mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg toabout 10 mg per kg. On the other hand, it may be necessary to usedosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 2 g of an activeingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical Compositions

For the treatment of any of the prostanoid mediated diseases compoundsof formula I may be administered orally, topically, parenterally, byinhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. In addition to the treatment of warm-bloodedanimals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., thecompound of the invention is effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavouring agents, colouring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed withwater-miscible solvents such as propylene glycol, PEGs and ethanol, oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol or polyethylene glycols may also be used.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Compounds of formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ambient temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound of formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.) Topical formulations may generally be comprised of apharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

Utilities

The ability of the compounds of formula I to interact with prostaglandinreceptors makes them useful for preventing or reversing undesirablesymptoms caused by prostaglandins in a mammalian, especially humansubject. This mimicking or antagonism of the actions of prostaglandinsindicates that the compounds and pharmaceutical compositions thereof areuseful to treat, prevent, or ameliorate in mammals and especially inhumans: Pain, fever and inflammation of a variety of conditionsincluding rheumatic fever, symptoms associated with influenza or otherviral infections, common cold, low back and neck pain, skeletal pain,post-partum pain, dysmenorrhea, headache, migraine, toothache, sprainsand strains, myositis, neuralgia, synovitis, arthritis, includingrheumatoid arthritis, degenerative joint diseases (osteoarthritis), goutand ankylosing spondylitis, bursitis, burns including radiation andcorrosive chemical injuries, sunburns, pain following surgical anddental procedures as well as immune and autoimmune diseases. Inaddition, such a compound may inhibit cellular neoplastictransformations and metastic tumor growth and hence can be used in thetreatment of cancer. Compounds of formula I may also be of use in thetreatment and/or prevention prostaglandin-mediated proliferationdisorders such as may occur in diabetic retinopathy and tumorangiogenesis. Compounds of formula I will also inhibitprostanoid-induced smooth muscle contraction by antagonizing contractileprostanoids or mimicking relaxing prostanoids and hence may be use inthe treatment of dysmenorrhea, premature labor, asthma and eosinophilrelated disorders. It will also be of use in the treatment ofAlzheimer's disease, the treatment of glaucoma, for the prevention ofbone loss (treatment of osteoporosis) and for the promotion of boneformation (treatment of fractures) and other bone diseases such asPaget's disease.

By virtue of its prostanoid or prostanoid antagonist activity, acompound of formula I will prove useful as an alternative toconventional non-steroidal anti-inflammatory drugs (NSAID'S)particularly where such non-steroidal anti-inflammatory drugs may becontraindicated such as in patients with peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; GI bleeding, coagulationdisorders including anemia such as hypoprothrombinemia, haemophilia orother bleeding problems; kidney disease; thrombosis, occlusive vasculardiseases; those prior to surgery or taking anti-coagulants. Compounds offormula I will also be useful as a cytoprotective agent for patientsunder chemotherapy.

Combinations with Other Drugs

Compounds of formula I will be useful as a partial or completesubstitute for conventional antiinflammatory or analgesic compounds inpreparations wherein they are presently co-administered with otheragents or ingredients. Thus in further aspects, the inventionencompasses pharmaceutical compositions for treating prostaglandin E₂mediated diseases as defined above comprising a non-toxictherapeutically effective amount of the compound of formula I as definedabove and one or more ingredients such as another pain relieverincluding acetaminophen or phenacetin; a COX-2 selective inhibitingagent; a conventional NSAID; a potentiator including caffeine; anH2-antagonist, aluminum or magnesium hydroxide, simethicone, adecongestant including phenylephrine, phenylpropanolamine,pseudophedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxyephedrine; anantiitussive including codeine, hydrocodone, caramiphen, carbetapentane,or dextramethorphan; another prostaglandin ligand including misoprostol,enprostil, rioprostil, ornoprostol or rosaprostol; a diuretic; asedating or non-sedating antihistamine. In addition, the inventionencompasses a method of treating prostaglandin E₂ mediated diseasescomprising: administration to a patient in need of such treatment anon-toxic therapeutically effective amount of the compound of formula I,optionally co-administered with one or more of such ingredients aslisted immediately above.

Methods of Synthesis

Compounds of the present invention can be prepared according to thegeneral synthesis schemes appearing in WO96/30358, or in accordance withU.S. Pat. No. 5,391,817, incorporated herein by reference in itsentirety. Alternativley, the compounds can be synthesized using thefollowing methods:

Method A

This method make use of Z precursor containing protected acid unit(AC(O)B). Suzuki's cross coupling between excess aryl dihalide of type 1and an appropriate boronic acid 2 led to the biaryl 3. In most cases,Pd(PPh₃)₄ is used as the catalyst, Na₂CO₃ or CsF as the base in arefluxing mixture of DME/H₂O (4/1). A second Suzuki's coupling between 3and the boronate 4 followed by acidic hydrolysis of the resulting ester5 (basic hydrolysis in the cases of methyl or ethyl ester) afforded thedesired acid 6. A second strategy involves the formation of the boronicacid 7 from the corresponding halide 3 and a subsequent Suzuki'scoupling with the aryl halide 8. Deprotection of the resulting ester 9followed by coupling with an appropriate sulfonamide using EDCI/DMAP ledto the acyl-sulfonamide 10.

Method B

In this method the acid group (AC(O)B) is introduce by Horner-Emmons (orWittig) condensation. Suzuki's coupling between the boronic acid 11 andthe aryl dihalide 1 led to the aldehyde 12 under previously describedconditions. The acid unit is introduce by a Horner-Emmons reaction toafford the diaryl halide 13 followed by cross coupling with the boronicacid 1 to give the desired ester 9. Alternatively, coupling between 12and 2 followed by a Horner-Emmons reaction on the resulting aldehyde 14,can also afford the ester 9.

Method C

Upon addition of an alkylating reagent (R-Hal) to the anion oftert-butyl ester 15, generated in presence of a hindered base,monosubstituted (16) esters were obtained. The ester (16) can be furthermodified as described in method A to give the desired a-substitutedacids 17.

Method D

For the synthesis of compounds in which the central heteroaryl Y is a2,4-thiazole or a 2,5-thiazole (21, 24) see the procedures described inthe following references; Nan'ya, S.; Ishida, H.; Kanie, K; Ito, N.;Butsugan, Y. J. Heterocyclic Chem. 1995, 32, 1299. Zhang, M. Q.;Haemers, A.; Vanden Berghe, D.; Pattyn, S. R.; Bolaert, W. J.Heterocyclic Chem. 1991, 28, 673. Gordon, T. D.; Singh, J.; Hansen, P.E.; Morgan, P. A. Tetrahedron Lett, 1993, 34, 1901.

Method E

For the synthesis of compounds in which the central heteroaryl Y is a2,4-oxazole or a 2,5-oxazole (28, 31) see the procedures described inthe following references; Huang, W.; Pei, J.; Chen, B.; Pei, W.; Ye, X.Tetrahedron, 1996, 52, 10131. Hammar, W. J.; Rustad, M. A. J.Heterocyclic Chem. 1981, 18, 885.

Method F

For the synthesis of compounds in which the central heteroaryl Y is a4,1-imidazole (37) see the procedures described in the followingreferences; Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J. Org.Chem. 1995, 60, 5678. Horne, D. A.; Yakushijin, K.; Büchi, G.Heterocycle 1994, 39, 139. For the synthesis of aryllead triacetatessee; Barton, D. H.; Finet, J. P.; Donnelly, D. M. X. J. Chem. Soc.Perkin T. 1 1992, 1365.

EXAMPLES

The species described herein can be made following the procedures setforth in the examples below, in which, unless otherwise stated:

The end products were analyzed by NMR, TLC and elementary analysis;

Intermediates were analyzed by NMR and TLC;

The compounds were purified by flash chromatography on silica gel,recrystallization and/or swish (suspension in a solvent followed byfiltration of the solid);

The course of reactions was followed by thin layer chromatography (TLC)and reaction times are given for illustration only; and

Some end products were converted to the sodium salt (dissolved in EtOHthen addition of NaOH aq.)

The following intermediates were prepared according to literatureprocedures:

(Phenylmethoxy)benzeneboronic acid: Johnson, C. R.; Johns, B. A. J. Org.Chem. 1997, 62, 6046-6050.

2,4-Dibromo-5-chlorothiophene: Gronowitz, H. Acta Chem. Scand. Ser. B,1976, 30, 439-445.

Lithium N-isopropylcyclohexylamnide; lithium tert-butyl acetyl:Paquette, L. A.; Ewing, G. D. J. Org. Chem. 1975, 40, 2965-2966.

Example 1 3-(2-{3-[5-Chloro-2-(phenylmethoxy)-3-pyridyl]phenyl}phenyl)propanoic acid (5)

Step 1; 2-(3-Bromophenyl)benzaldehyde

A mixture of 2-formylbenzeneboronic acid (15.35 g, 102 mmol),1,3-dibromobenzene (75.25 g, 319 mmol), 2M Na₂CO₃ (150 mL) and (Ph₃P)₄Pd(2.81 g, 24 mmol) in DME (600 mL) was heated to 80° C. for 4 h. Themixture was cooled to r.t., quenched with 1N HCl (or aqueous NH₄Cl) andextracted with EtOAc. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(Tol:Hex, 0:1 to 1:1) provided the desired material as a yellow solid(21.3 g, 80%). ¹H NMR (acetone-d₆) δ 7.4-7.8 (7H, m), 7.97 (1H, ddd),9.95 (1H, s).

Step 2; Ethyl (E)-3-[2-(3-bromophenyl)phenyl]prop-2-enoate

To 2-(3-bromophenyl)benzaldehyde (6.67 g, 25.5 mmol) and triethylphosphonoacetate (6.89 g, 30.7 mmol) in Tol (90 mL) at 0° C. was addedNaH (38.7 mmol). The reaction mixture was stirred at r.t. overnight. Thereaction mixture was poured into aqueous NH₄Cl and extracted twice withEt₂O. The combined organic extracts were washed (H₂O:brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(Tol) afforded the desired material as a colorless oil (8.01 g, 95%). ¹HNMR (acetone-d₆) δ 1.25 (3H, t), 4.16 (₂H, q), 6.50 (1H, d), 7.3-7.7(8H, m), 7.89 (1H, m).

Step 3; (E)-3-[2-(3-bromophenyl)phenyl]prop-2-enoic acid

The previous ester (8.01 g, 24.2 mmol) was hydrolyzed in THF:MeOH:2NLiOH (80 mL :40 mL :40 mL). After being stirred at r.t. overnight, thereaction mixture was poured into 1N HCl (or H₂O:AcOH 10%) and extractedwith EtOAc. The organic layer was washed with brine, dried (MgSO₄),filtered and concentrated. Purification by a swish (Hex:EtOAc, 1:1)provided the title compound as a white crystalline solid (6.33 g, 86%).¹H NMR (acetone-d₆) δ 6.49 (1H, d), 7.3-7.7 (8H, m), 7.90 (1H, m).

Step 4; 3-[2-(3-Bromophenyl)phenyl]propanoic acid

To the previous acid (7.19 g, 23.7 mmol) suspended in EtOAc (125 mL) wasadded PtO₂ (262 mg, 1.14 mmol). After being sonicated for 2 h andstirred at r.t. for 2 days under a hydrogen atmosphere, the suspensionwas filtered over Celite and concentrated. Purification by a swish (Hex)afforded the title compound as a white solid (6.27 g, 86%). ¹H NMR(acetone-d₆) δ 2.46 (2H, t), 2.88 (2H, t), 7.18 (1H, dd), 7.28 (1H, td),7.3-7.4 (4H, m), 7.52 (1H, t), 7.56 (1H, ddd).

Step 5; Methyl3-{2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phenyl}propanoate

After esterification of the previous acid (1.72 g, 5.64 mmol) in ether(20 mL) with an excess of diazomethane at 0° C., the solution was dried(MgSO₄), filtered and concentrated. To this crude ester in DMF (20 mL),diboron pinacol ester (1.57 g, 6.20 mmol), PdCl₂(dppf) (138 mg, 0.169mmol) and KOAc (1.78 g, 18.14 mmol) were added. After heating at 80° C.for 2 h, the mixture was poured into water and extracted twice withEt₂O. The combined organic extracts were washed (H₂O:brine), dried(MgSO₄), filtered and concentrated. Purification by flash chromatography(Tol:Hex:EtOAc, 1:0:0 to 0:4:1) afforded the desired material as ayellow oil (1.42 g, 69%). ¹H NMR (acetone-d₆) δ 1.33 (12H, s), 2.45 (2H,t), 2.89 (2H, t), 3.54 (3H, s), 7.18 (1H, dd), 7.2-7.4 (3H, m), 7.46(2H, m), 6.67 (1H, m), 7.75 (1H, m).

Step 6; 3-Bromo-5-chloro-2-(phenylmethoxy)pyridine

A mixture of 3-bromo-5-chloropyridin-2-ol (50 g, 242 mmol), benzylbromide (32 mL, 269 mmol) and Ag₂CO₃ (60 g, 218 mmol) in benzene (500mL) was refluxed for 1 h. The suspension was filtered over Celite andconcentrated. The crude material was put under vacuo overnight to obtainthe title compound as a yellow solid. ¹H NMR (acetone-d₆) δ 5.44 (2H,s), 7.2-7.4 (3H, m), 7.50 (2H, m), 8.07 (1H, d) 8.16 (1H, d).

Step 7; Methyl3-(2-{3-[5-chloro-2-(phenylmethoxy)-3-pyridyl]phenyl}phenyl) propanoate

A mixture of methyl ester (404 mg, 1.10 mmol) of step 5 in this example,3-bromo-5-chloro-2-(phenylmethoxy)pyridine (650 mg, 2.18 mmol),PdCl₂(dppf) (33 mg, 0.04 mmol) and 2M Na₂CO₃ (2.4 mL) in DMF (6 mL) washeated to 80° C. overnight. The mixture was quenched with 1N HCl andextracted twice with Et₂O. The combined organic extracts were washed(H₂O:brine), dried (MgSO₄), filtered and concentrated. Purification byflash chromatography (Tol) afforded the desired material as a whitesolid (394 mg, 78%). ¹H NMR (acetone-d₆) δ 2.41 (2H, t), 2.89 (2H, t),3.50 (3H, s), 5.45 (2H, s), 7.15 (1H, dd), 7.2-7.5 (9H, m), 7.52 (1H,dd), 7.6-7.7 (2H, m), 7.88 (1H, d), 8.16 (1H, d).

Step 8;3-(2-{3-[5-Chloro-2-(phenylmethoxy)-3-pyridyl]phenyl}phenyl)propanoicacid

As described in Example 1 (step 3), the previous ester (394 mg, 0.86mmol) was hydrolyzed in THF:MeOH:2N LiOH (4 mL:2 mL:2 mL). Purificationby a swish (Hex:EtOAc) afforded the title compound as a white solid (360mg, 94%). ¹H NMR (acetone-d₆) δ 2.42 (2H, t), 2.91 (2H, t), 5.45 (2H,s), 7.16 (1H, dd), 7.2-7.4 (9H, m), 7.52 (1H, td), 7.6-7.7 (2H, m), 7.89(1H, d), 8.16 (1H, d).

Example 2 (E)-3-(2-{3-[2-(Phenylmethxoy)phenyl]phenyl}phenyl)prop-2-enoic acid (7)

Step 1: Ethyl(E)-3-(2-{3-[2-(phenylmethoxy)phenyl]phenyl}phenyl)prop-2-enoate

As described in Example 1 (step 1), a mixture of 2-(phenylmethoxy)benzeneboronic acid (545 mg, 2.39 mmol), ethyl(E)-3-[2-(3-bromophenyl)phenyl]prop-2-enoate bromide (390 mg, 1.18 mmol)of Example 1 (step 2), 2M Na₂CO₃ (3.5 mL) and (Ph₃P)₄Pd (66 mg, 0.06mmol) in DME (7 mL) was heated to 80° C. for 2 h. Purification by flashchromatography (Tol) provided the desired material as a yellow solid(485 mg, 95%). ¹H NMR (acetone-d₆) δ 2.04 (3H, t), 4.12 (2H, q), 5.16(2H, s), 6.51 (1H, d), 7.07 (1H, td), 7.20 (1H, dd), 7.2-7.4 (8H, m),7.4-7.5 (4H, m), 7.6-7.7 (2H, m), 7.79 (1H, d) and 7.89 (1H, dd).

Step 2: (E)-3-(2-{3-[2-(Phenylmethoxy)phenyl]phenyl}phenyl)prop-2-enoicacid

The previous ester (483 mg, 1.11 mmol) was hydrolyzed in THF:MeOH:2NLiOH (4 mL:2 mL:2 mL) at 50° C. for 1 h. Purification by a swish(Hex:Et₂O) afforded the desired material as a white solid (419 mg, 93%).¹H NMR (acetone-d₆) δ 5.15 (2H, s), 6.49 (1H, d), 7.05 (1H, td), 7.20(1H, dd), 7.2-7.4 (8H, m), 7.4-7.5 (4H, m), 7.60 (2H, m), 7.80 (1H, d)and 7.89 (1H, dd).

Example 3 (E)-3-(2-{5-[2-(Phenylmethoxy)phenyl]-3-pyridyl}phenyl)prop-2-enoic acid (8)

Step 1; 2-(5-Bromo-3-pyridyl)benzaldehyde

As described in Example 1 (step 1), a mixture of 2-formylbenzeneboronicacid (2.00 g, 13.3 mmol), 3,5-dibromopyridine (9.52 g, 40.2 mmol), 2MNa₂CO₃ (17 mL) and (Ph₃P)₄Pd (762 mg, 0.66 mmol) in DME (80 mL) washeated to 80° C. for 12 h. Purification by flash chromatography(Tol:EtOAc, 1:0 to 19:1) provided the desired material as a yellow oil(2.85 g, 82%). ¹H NMR (acetone-d₆) δ 7.56 (1H, m), 7.68 (1H, t), 7.79(1H, td), 8.03 (1H, dd), 8.11 (1H, t), 8.60 (1H, d), 8.74 (1H, d), 10.01(1H, s).

Step 2; 2-{5-[2-(Phenylmethoxy)phenyl]-3-pyridyl}benzaldehyde

As described in Example 1 (step 1), a mixture of the previous bromide(507 mg, 1.93 mmol, step 1), 2-(phenylmethoxy)benzeneboronic acid (638mg, 2.80 mmol), 2M Na₂CO₃ (3.5 mL) and (Ph₃P)₄Pd (102 mg, 0.09 mmol) inDME (10 mL) was heated to 80° C. for 6 h. Purification by flashchromatography (Tol:EtOAc, 9:1) provided the desired material as ayellow oil (642 mg, 91%). ¹H NMR (acetone-d₆) δ 5.19 (2H, s), 7.1-7.4(9H, m), 7.51 (1H, dd), 7.63 (1H, t), 7.74 (1H, td), 8.01 (1H, dd), 8.06(1H, t), 8.55 (1H, d), 8.83 (1H, d), 10.03 (1H, s).

Step 3;(E)-3-(2-{5-[2-(Phenylmethoxy)phenyl]-3-pyridyl}phenyl)prop-2-enoic acid

As described in Example 1 (step 2), a mixture of the previous aldehyde(640 mg, 1.75 mmol, step 2), triethyl phosphonoacetate (420 uL, 2.12mmol) and NaH (2.7 mmol) in Tol (6 mL) was stirred at rt for 6 h. Thecrude material was not purified. According to the procedure described instep 8 of Example 1, the crude ester was hydrolyzed in THF:MeOH:2N LiOH(6 mL:3 mL:3 mL). Purification by a swish (Hex:EtOAc) afforded thedesired material as a white solid (641 mg, 90%). ¹H NMR (acetone-d₆) δ5.15 (2H, s), 6.52 (1H, d), 7.09 (1H, t), 7.2-7.4 (7H, m), 7.42 (1H, m),7.50 (4H, m), 7.94 (2H,m), 8.42 (1H,d) 8.78 (1H, d).

Example 4(E)-3-(2-{3-[2-(Phenylmethoxy)phenyl]phenyl}phenyl)-N-(2-thienylsulfonyl)prop-2-enamide(55)

To (E)-3-(2-{3-[2-(Phenylmethoxy)phenyl]phenyl}phenyl)prop-2-enoic acid(210 mg, 0.52 mmol) of Example 2 (step 2), 2-thiophenesulfonylamide (121mg, 0.74 mmol) and DMAP (250 mg, 2.04 mmol) in CH₂Cl₂ (3 mL) was addedEDCI (142 mg, 0.74 mmol). After stirring at r.t. for 2 days, thereaction mixture was poured into 1N HCl (or aqueous AcOH) and extractedwith EtOAc. The organic layer was washed with brine, dried (MgSO₄),filtered and concentrated. Purification by flash chromatography(Tol:EtOAc:AcOH, 1:0:0 to 20:1:0.1) and recrystallization (Hex:CH₂Cl₂)provided the desired material as a white solid (161 mg, 56%). ¹H NMR(acetone-d₆) δ 5.13 (2H, s), 6.72 (1H, d), 7.04 (1H, td), 7.1-7.2 (2H,m), 7.2-7.4 (8H, m), 7.4-7.5 (4H, m), 7.55 (1H, t), 7.62 (1H, dt),7.7-7.8 (3H, m) and 7.92 (1H, dd).

Example 52-Methyl-3-(2-{4-[3-(3-methylphenoxy)propoxy]phenyl}phenyl)-N-(2-thienylsulfonyl)propanamide(84)

Step 1; 3-(4-Bromophenoxy)propan-1-ol

To 4-bromo phenol (151 g; 0.87 mol) and 3-bromo propanol (120 mL; 1.3mol) in 1.2 L of acetone was added portionwise K₂CO₃ (152 g; 1.1 mol).Final mixture was refluxed for 12 h, cool to rt, filtered andconcentrated. Distillation (0.2 mm Hg; 120° C.) afforded the desiredmaterial as a colorless oil (173 g; 86%). ¹H NMR (acetone-d₆) δ 1.95(2H, m), 3.58 (1H, t), 3.67 (2H, m), 4.08 (2H, t), 6.90 (2H, d), 7.41(2H, d).

Step 2; 1-Bromo-4-[3-(3-methylphenoxy)propoxy]benzene

To a solution of the previous alcohol (10.1 g; 44 mmol) in 110 mL ofCH₂Cl₂ at −50° C. was added NEt₃ (9.0 mL; 65 mmol) then dropwise MsCl(4.0 mL; 52 mmol). Final mixture was allowed to reach 0° C. then pouredin saturated aqueous NaHCO₃ and extracted with CH₂Cl₂ (2×). The combinedorganic extracts were dried over, filtered and concentrated to affordthe mesylate, which was used without further purification. To a solutionof m-cresol (6.6 g; 61 mmol) in 130 mL of DMF was added portionwise NaH(1.6 g; 80%; 52 mmol). The mixture was stirred 1 h at rt then themesylate was added. Final mixture was stirred 12 h at rt then was pouredin H₂O and extracted with Et₂O (3×). The combined organic extracts werewashed with H₂O (2×), brine, dried over MgSO₄, filtered andconcentrated. The excess m-cresol was removed by basic extraction (NaOH1n; Hex) to afford the title compound as a white solid (13.5 g; 96%). ¹HNMR (acetone-d₆) δ 2.22 (2H, m), 2.27 (3H, s), 4.17 (4H, m), 6.74 (3H,m), 6.92 (2H, dd), 7.13 (1H, t), 7.41 (2H, dd).

Step 3; Tert-butyl3-(2-{4-[3-(3-methylphenoxy)propoxy]phenyl}phenyl)propanoate

To a solution of the previous aryl bromide (6.16 g; 19.1 mmol) in 70 mLof DME at −78° C. was added dropwise n-BuLi (8.4 mL; 2.5 M; 21 mmol).After stirring 30 min at −78° C., triiso-propyl boronate (4.4 mL; 19.1mmol) was added and the solution was warmed to rt and stirred for 2 h.To this solution of boronate was added Na₂CO₃ (28 mL; 2 M; 56 mmol),Tert-butyl 3-(2-bromophenyl)propanoate (Example 4; step 1; 4.19 g; 14.7mmol) and Pd(PPh₃)₄ (0.27 g; 0.24 mmol). The final mixture was stirredat 85° C. for 6 h then was poured in HCl (1N) and extracted with EtOAc(2×). The combined organic extracts were washed brine, dried overNa₂SO₄, filtered and concentrated. Flash chromatography (Hex:EtOAc; 7:3)yielded the title compound as a yellow oil (6.69 g; 78%). ¹H NMR(acetone-d₆) δ 6 1.33 (9H, s), 2.25-2.35 (7H, m), 2.87 (2H, t),4.15-4.25 (4H, m), 6.76 (3H, m), 7.03 (2H, dd), 7.15 (2H, m), 7.2-7.3(5H, m).

Step 4; Tert-butyl2-methyl-3-(2-{4-[3-(3-methylphenoxy)propoxy]phenyl}phenyl)propanoate

A solution of the previous ester (2.76 g, 6.17 mmol) in THF (10 mL) wasadded to a solution of lithium N-isopropylcyclohexylamide (56 mL; 0.14M; 7.8 mmol) in THF at −78° C. then 30 min later, iodomethane (1.3 mL,21 mmol). The solution was warmed slowly (1.5 h) at 0° C., then pouredin 1N HCl and extracted with EtOAc (2×). The combined organic extractswere washed with brine, dried over MgSO₄, filtered and concentrated.Flash chromatography (Hex:EtOAc; 7:3) afforded the title compound as ayellow oil (2.47 g; 86%). ¹H NMR (acetone-d₆) δ 0.88 (3H, d), 1.27 (9H,s), 2.2-2.4 (6H, m), 2.68 (1H, dd), 2.93 (1H, dd), 4.20 (2H, t), 4.24(2H, t), 6.76 (3H, m), 7.03 (2H, dd), 7.15 (2H, m), 7.24 (5H, m).

Step 5:2-methyl-3-(2-{4-[3-(3-methylphenoxy)propoxy]phenyl}phenyl)propanoicacid

To a solution of the previous ester (1.33 g; 2.88 mmol) in 9 mL ofCH₂Cl₂ at 0° C. was added TFA (4.5 mL; 58 mmol). The resulting solutionwas stirred at rt until all starting material was consumed as monitoredby TLC. Two co-evaporation with Tol followed by flash chromatography(Tol:EtOAc:AcOH; 10:0.5:0.05) afforded the desired acid as a colorlessoil (1.04 g; 89%). ¹H NMR (acetone-d₆) δ 0.92 (3H, d), 2.27 (5H, m),2.52 (1H, m), 2.69 (1H, dd), 3.05 (1H, dd), 4.20 (2H, t), 4.24 (2H, t),6.76 (3H, m), 7.02 (2H, dd), 7.1-7.3 (7H, m).

Step 62-Methyl-3-(2-{4-[3-(3-methylphenoxy)propoxy]phenyl}phenyl)-N-(2-thienylsulfonyl)propanamide

To a solution of the previous acid (453 mg; 1.12 mmol) in 10 mL ofCH₂Cl₂ at 0° C. was added oxalyl chloride (0.30 mL; 3.3 mmol) then acatalytic amount of DMF (35 μL). The resulting solution was stirred atrt was monitored by MeOH quench/TLC. Two co-evaporation with Tolafforded the desired acid chloride, which was used without any furtherpurification. The acid chloride was dissolved in 7 mL of CH₂Cl₂, cooledto 0° C., then DIPEA (580 mL; 3.3 mmol) and and 2-thiophenesulfonylamide(222 mg, 1.4 mmol) were added simultaneously. The resulting solution wasstirred at rt for 12 h, quenched with 25 mL MeOH, concentrated, pouredin H₂O (10% AcOH) and extracted with EtOAc (2×). The combined organicextracts were washed brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (CH₂Cl₂:MeOH 2.5%) afforded the titlecompound (350 mg; 56%). The carboxylic acid was converted to it'scorresponding sodium salt (EtOH: NaOH 1N). ¹H NMR (acetone-d₆) δ 0.93(3H, d), 2.27 (5H, m), 2.60-2.75 (2H, m), 2.91 (1H, dd), 4.22 (4H, m),6.77 (3H, m), 7.01 (2H, d), 7.05-7.25 (8H, m), 7.74 (1H, dd), 7.94 (1H,dd).

Example 6(E)-3-{2-[3-(3-{3-[2-(7-Chloro(2-quinolyl))vinyl]phenoxy}propoxy)phenyl]phenyl}-N-(2-thienylsulfonyl)propanamide(98)

Step 1: 3-(3-Bromophenoxy)propan-1-ol

Prepared as described in Example 5 (step 1) from 3-bromo phenol. ¹H NMR(acetone-d₆) δ 1.95 (2H, m), 3.69 (3H, m), 4.12 (2H, t), 6.93 (1H, dd),7.08 (2H, m), 7.23 (1H, t).

Step 2: {3-[3-(3-Bromophenoxy)propoxy]phenyl}methan-1-ol

Prepared as described in Example 5 (step 2) from the correspondingmesylate of the previous alcohol and 3-hydroxymethyl phenol. ¹H NMR(acetone-d₆) δ 2.23 (2H, quint.), 4.18 (5H, m), 4.59 (2H, d), 6.81 (1H,dd), 6.90 (1H, d), 6.96 (2H, m), 7.05-7.25 (4H, m).

Step 3; 3-{3-[3-(Hydroxymethyl)phenoxy]propoxy}benzeneboronic acid

To a solution of the previous aryl bromide (15.6 g; 46 mmol) in 200 mLof THF at −78° C. was added dropwise n-BuLi (40 mL; 2.5 M; 100 mmol).After stirring 45 min at −78° C., triiso-propyl boronate (27 mL; 116mmol) was added, the solution was warmed to rt and stirred for 9 h. HCl(1N) was added until the pH=1, the resulting mixture was diluted withH₂O and extracted with EtOAc. The organic extract was washed with H₂O(2×), brine, dried over Na₂SO₄, filtered and concentrated. Purificationby swish (Hex:EtOAc:H₂O) yielded the title compound as a white solid(5.3 g; 38%). ¹H NMR (acetone-d₆) δ

Step 4: Tert-butyl3-[2-(3-{3-[3-(hydroxymethyl)phenoxy]propoxy}phenyl)phenyl]propanoate

The previous boronic acid (5.26 g; 17.4 mmol), tert-butyl3-(2-bromophenyl) propanoate (5.99 g; 21 mmol), Pd(PPh₃)₄ (1.21 g; 1.1mmol) and Na₂CO₃ (20 mL; 2 N; 40 mmol) were combined in 100 mL of DME.Nitrogen was bubbled in the suspension for 15 min then it was stirred at80° C. for 8 h. The mixture was cooled to rt, poured in saturatedaqueous NH₄Cl then extracted with EtOAc (2×). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated. Flashchromatography (Tol:EtOAc; 90:10) afforded the title compound (5.18 g;64%). ¹H NMR (acetone-d₆) δ 1.33 (9H, s), 2.26 (2H, m), 2.34 (2H, m),2.88 (2H, t), 4.09 (1H, t), 4.20 (2H, t), 4.25 (2H, t), 4.58 (2H, d),6.81 (1H, dd), 6.85-7.00 (5H, m), 7.1-7.4 (6H, m).

Step 5; Tert-butyl3-(2-{3-[3-(3-formylphenoxy)propoxy]phenyl}phenyl)propanoate

To a solution of the previous benzyl alcohol (5.18 g; 11.2 mmol) in 75mL of EtOAc at 0° C. was added MnO₂ (30.2 g; 0.34 mol) portionwise. Thesuspension was stirred at rt for 4 h, filtered on Celite, andconcentrated to yield the title compound (4.30 g; 84%). %). ¹H NMR(acetone-d₆) δ 1.33 (9H, s), 2.32 (4H, m), 2.87 (2H, t), 4.29 (4H, m),6.90 (2H, m), 6.98 (1H, m), 7.17 (1H, m), 7.2-7.4 (5H, m), 7.49 (3H, m),9.99 (1H, s).

Step 6; Tert-butyl(E)-3-{2-[3-(3-{3-[2-(7-chloro-2-guinolyl)vinyl]phenoxy}propoxy)phenyl]phenyl}propanoate

To a suspension of (7-chloroquinolin-2-yl)methyl triphenylphosponiumbromide (1.71 g; 3.3 mmol) in 15 mL THF at −78° C. was added dropwiset-BuOK (3.6 mL; 1.0 M; 3.6 mmol). The mixture was stirred at −78° C. for15 min, at 0° C. for 30 min then was cooled down to −78° C. A solutionof the previously described aldehyde (1.04 g; 2.3 mmol) in 3 mL THF wascannulated and the final mixture was stirred 5 h at 0° C. It was pouredin H₂O: AcOH 10% and extracted with EtOAc (2×). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated. Flashchromatography (Tol then Tol:EtOAc; 95:5) afforded the title compound(1.39 g; 98%). ¹H NMR (acetone-d₆) δ 1.32 (9H, s), 2.32 (4H, m), 2.88(2H, t), 4.29 (4H, q), 6.85-7.00 (4H, m), 7.1-7.4 (8H, m), 7.44 (1H, d),7.51 (1H, dd), 7.79 (1H, d), 7.85 (1H, d), 7.92 (1H, d), 7.99 (1H, dd),8.30 (1H, d).

Step 7: (E)-3-{2-[3-(3-{3-[2-(7-chloro-2-quinolyl)vinyl]phenoxy}propoxy)phenyl]phenyl}propanoic acid

To a solution of the previous ester (1.39 g; 2.24 mmol) in 60 mL of Tolwas added AlCl₃ (0.90 g; 6.76 mmol). The suspension was stirred for 12h, poured in H₂O and extracted with EtOAc (2×). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Flash chromatography (Tol:EtOAc:AcOH; 95:5:1) afforded thetitle compound (894 mg; 71%). ¹H NMR (acetone-d₆) δ 2.28 (2H, m), 2.48(2H, m), 2.94 (2H, t), 4.28 (4H, m), 6.90 (1H, m), 6.97 (3H, m), 7.1-7.4(8H, m), 7.50 (2H, m), 7.82 (2H, m), 7.90 (1H, d), 8.02 (1H, d), 8.28(1H, d).

Step 8: (E)-3-{2-[3-(3-{3-[2-(7-chloro(2-quinolyl))vinyl]phenoxy}propoxy)phenyl]phenyl}-N-(2-thienylsulfonyl)propanamide

To a mixture of the previous acid (696 mg; 1.23 mmol),2-thiophenesulfonylamide (404 mg; 2.48 mmol) and DMAP (233 mg; 1.91mmol) in 6 mL of CH₂Cl₂ was added EDCI (358 mg; 1.87 mmol). The mixturewas stirred at rt for 12 h, poured in saturated aqueous NH4Cl andextracted with CH₂Cl₂ (2×). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated. Flash chromatography(Tol:EtOAc:AcOH; 95:5:1) afforded the title compound (614 mg; 75%). ¹HNMR (acetone-d₆) δ 2.28 (2H, m), 2.55 (2H, t), 2.88 (2H, t), 4.26 (4H,q), 6.83 (1H, m), 6.88 (1H, m), 6.95 (2H, m), 7.10-7.35 (9H, m), 7.44(1H, d), 7.49 (1H, dd), 7.75-7.90 (5H, m), 8.00 (1H, d), 8.26 (1H, d).

Example 7(E)-3-(2-{3-[2-(7-Chloro(2-quinolyl))vinyl]phenyl}phenyl)-N-(2-thienylsulfonyl)prop-2-enamide(103)

Step 1: (E)-2-{3-[2-(7-chloro-2-quinolyl)vinyl]phenyl}benzaldehyde

Prepared as described in Example 1 (step 1) from(E)-2-[2-(3-bromophenyl)vinyl]-7-chloroquinoline (prepared as describedExample 8 (step 6), from 3-bromobenzaldehyde) and 2-formylbenzeneboronic acid (1.5 eq.). Title compound was purified by swish(Hex: CH₂Cl₂). ¹H NMR (CDCl₃) δ 7.3-7.6 (6H, m), 7.6-7.8 (6H, m),8.0-8.1 (3H, m), 10.03 (1H, d).

Step 2: Ethyl(E)-3-(2-{3-[2-(7-chloro-2-quinolyl)vinyl]phenyl}phenyl)prop-2-enoate

To a solution of triethylphosphono acetate (2.16 g; 9.66 mmol) in 100 mLof THF at 0° C. was added NaH (441 mg; 11.0 mmol). The reaction mixturewas stirred for 30 min at 0° C., a solution of the previous aldehyde(3.40 g; 9.20 mmol) in 10 mL THF was then cannulated and the finalmixture was stirred at rt for 12 h. The reaction was quenched usingsaturated aqueous NH₄Cl, the THF was removed in vacuo, extracted withCH₂Cl₂. The organic phase was washed with H₂O, saturated aqueous NaHCO₃,dried over Na₂SO₄, filtered and concentrated. Flash chromatography(Tol:EtOAc; 95:5) afforded the title compound as a yellow solid (3.54 g;88%). ¹H NMR (CDCl₃) δ 1.25 (3H, t), 4.20 (2H, q), 6.45 (1H, d), 7.1-7.5(8H, m), 7.55 (3H, m), 7.67 (2H, m), 7.83 (1H, d), 7.89 (1H, d), 8.05(1H, d).

Step 3:(E)-3-(2-{3-[2-(7-chloro-2-quinolyl)vinyl]phenyl}phenyl)prop-2-enoicacid

To a solution of the previous ester (3.54 g; 8.05 mmol) in 50 mL of1,4-dioxane was added 4 mL of NaOH (10 M). The mixture was stirred at90° C. for 12 h, cooled down and acidified using HCl 10%. The residualprecipitate (HCl salt of the quinoline) was filtered, washed with Et₂Oand dried in vacuo to yield the title compound (3.5 g; 97%) which wasused without further purification. ¹H NMR (dmso-d₆) δ 6.49 (1H, d), 7.28(1H, d), 7.4-8.0 (14H, m), 8.38 (1H, d).

Step 4:(E)-3-(2-{3-[2-(7-chloro(2-quinolyl))vinyl]phenyl}phenyl)-N-(2-thienylsulfonyl)prop-2-enamide

Prepared as described in Example 4, from the previous acid,2-thiophenesulfonamide. ¹H NMR (dmso-d₆) δ 6.63 (1H, d), 7.15 (1H, m),7.25 (1H, d), 7.4-8.0 (16H, m), 8.40 (1H, d).

Example 8(E)-3-[2-(3,4-Dichlorophenyl)phenyl]-N-(2-thienylsulfonyl)prop-2-enamide(104)

Step 1; Methyl (E)-3-[2-(3,4-dichlorophenyl)phenyl]prop-2-enoate

A mixture of 3,4-dichlorophenyl boronic acid (3.95 g; 25 mmol), ethyl2-bromocinnamate (2.0 g; 8.3 mmol), CsF (6.30 g; 50 mmol) and Pd(PPh₃)₄(1.21 g; 1.1 mmol) in 40 mL of DME was stirred at 100° C. for 10 h. Themixture was cooled to rt, poured in saturated aqueous NH₄Cl thenextracted with EtOAc (2×). The combined organic extracts were dried overNa₂SO₄, filtered and concentrated. Flash chromatography (Tol) andsubsequent swish (Hex) afforded the title compound (1.71 g; 47%). ¹H NMR(CDCl₃) δ 3.75 (3H, s), 6.39 (1H, d), 7.12 (1H, dd), 7.30 (1H, m), 7.42(3H, m), 7.50 (1H, d), 7.62 (1H, d), 7.68 (1H, m).

Step 2; (E)-3-[2-(3,4-dichlorophenyl)phenyl]prop-2-enoic acid

Prepared as described in Example 2 (step 2) from the previous ester. ¹HNMR (CDCl₃) δ 6.40 (1H, d), 7.11 (1H, dd), 7.32 (1H, dd), 7.4-7.5 (4H,m), 7.70 (2H, m).

Step 3;(E)-3-[2-(3,4-dichlorophenyl)phenyl]-N-(2-thienylsulfonyl)prop-2-enamide

Prepared as described in Example 4 from the previous acid. ¹H NMR(CDCl₃) δ 6.44 (1H, d), 7.04 (1H, dd), 7.10 (1H, dd), 7.3-7.5 (5H, m),7.66 (3H, m), 7.90 (1H, dd). HRMS (FAB⁺) m/z calcd for C₁₉H₁₄Cl₂NO₃S₂(M+H⁺): 437.9792, found 437.9791.

ELEMENTARY ANALYSIS OF REPRESENTATIVE COMPOUNDS Calculate (%) Observed(%) Molecular Formula C H N C H N 1 C₂₈H₂₁Cl₂NaO₃.H₂O 65.00 4.48 65.284.39 2 C₂₉H₂₅NaO₃.H₂O 75.31 5.88 75.61 5.71 3 C₂₆H₂₁NaO₃S.H₂O 68.71 5.1068.6 5.00 4 C₂₆H₂₁NaO₃S.0.5H₂O 70.13 4.93 69.93 4.94 5C₂₇H₂₁ClNNaO₃.4.5H₂O 59.29 5.53 2.56 59.30 5.32 2.54 7 C₂₈H₂₁NaO₃.1.5H₂O73.84 5.31 73.60 5.11 8 C₂₇H₂₁NO₃ 79.59 5.19 3.44 79.37 5.30 3.41 9C₂₆H₁₉Cl₂NaO₃S.H₂O 59.66 4.04 59.49 4.26 11 C₂₅H₁₉NaO₂.0.5H₂O 78.31 5.2677.79 5.23 12 C₂₁H₁₇NaO₂ 77.76 5.28 77.40 5.96 13 C₂₉H₂₅NaO₃.H₂O 75.315.88 75.85 5.68 14 C₂₁H₁₅Cl₂NaO₂0.5H₂O 62.70 4.01 62.22 3.93 15C₂₆H₂₁NaO₃S.0.5H₂O 70.10 4.98 70.21 5.30 16 C₂₈H₂₃NaO₃.0.5H₂O 76.52 5.5076.35 5.50 17 C₂₈H₂₃NaO₃.0.5H₂O 76.52 5.50 76.08 5.51 18 C₃₂H₂₅NaO₃.H₂O77.09 5.46 77.41 5.41 19 C₂₆H₁₉NaO₃S.1.5H₂O 67.67 4.80 68.00 4.69 20C₂₆H₁₉NaO₃S.1.5H₂O 67.67 4.80 67.82 4.91 21 C₂₈H₂₃NaO₃.0.5H₂O 76.52 5.5076.75 5.90 53 C₃₂H₂₅NO₄S₂ 69.67 4.57 2.54 69.20 4.63 2.54 72C₂₈H₂₆NNaO₃S₃.0.5H₂O 60.91 4.93 2.54 61.08 4.77 2.72 73C₂₈H₂₆NNaO₃S₃0.5H₂O 60.91 4.93 2.54 61.05 4.68 2.51 75 C₃₇H₃₆NNaO₅S₃64.05 5.23 2.02 63.97 5.56 1.99 76 C₃₇H₃₆NNaO₆S₃.0.5H₂O 61.82 5.19 1.9561.74 5.26 1.86 77 C₂₉H₂₈NNaO₅S₂ 62.46 5.06 2.51 62.18 5.11 2.52 79C₃₂H₂₅N₂NaO₃S₂.0.5H₂O 66.08 4.51 4.82 65.83 4.75 4.72 80C₃₅H₃₂NNaO₃S₃.H₂O 64.49 5.22 2.15 64.55 5.28 2.10 81C₃₀H₃₀NNaO₅S₂.0.5H₂O 62.05 5.38 2.41 61.80 5.32 2.38 82 C₃₈H₃₈NNaO₆S₂65.97 5.54 2.02 65.95 5.20 2.14 83 C₃₉H₃₂ClN₂NaO₅S₂.H₂O 62.52 4.57 3.7462.66 4.49 3.65 84 C₃₆H₃₃ClNNaO₅S₂ 63.38 4.88 2.05 63.70 4.83 2.21 85C₄₁H₃₆NNaO₆S₂.3H₂O 63.14 5.43 1.80 63.14 4.95 1.96 86 C₂₉H₂₈NNaO₅S₂.H₂O60.51 5.25 2.43 60.88 5.00 2.53 87 C₂₉H₂₆NNaO₅S₂.0.5H₂O 61.69 4.82 2.4861.59 5.01 2.52 88 C₂₉H₂₇N₂NaO₄S₂.H₂O 60.82 5.10 4.89 60.80 5.04 5.01 89C₂₉H₂₂ClN₂NaO₄S₂.H₂O 57.76 4.01 4.64 57.95 3.94 4.63 90C₂₀H₁₈NNaO₃S₃.H₂O 52.50 4.41 3.06 52.77 4.50 3.17 91 C₂₀H₁₈NNaO₅S₃.H₂O49.06 4.12 2.86 49.07 4.03 2.87 92 C₂₉H₂₆Br₂ClN₂NaO₅S₂.H₂O 47.49 3.851.91 47.55 3.64 1.93 93 C₃₉H₃₂ClN₂NaO₅S₂.1.5H₂O 61.70 4.46 3.70 61.774.65 3.69 94 C₃₀H₂₂ClN₂NaO₃S₂.H₂O 60.15 4.03 4.68 59.95 4.05 4.56

Assays for Determining Biological Activity

The compounds of Formula I can be tested using the following assays todetermine their prostanoid antagonist or agonist activity in vitro andin vivo and their selectivity. The prostaglandin receptors investigatedwere DP, EP₁, EP₂, EP₃, EP₄, FP, IP and TP.

Stable Expression of Prostanoid Receptors in the Human Embryonic Kidney(HEK) 293(Ebna) Cell Line

Prostanoid receptor cDNAs corresponding to full length coding sequenceswere subcloned into the appropriate sites of mammalian expressionvectors and transfected into HEK 293(ebna) cells. HEK 293(ebna) cellsexpressing the individual cDNAs were grown under selection andindividual colonies were isolated after 2-3 weeks of growth using thecloning ring method and subsequently expanded into clonal cell lines.

Prostanoid Receptor Binding Assays

HEK 293(ebna) cells are maintained in culture, harvested and membranesare prepared by differential centrifugation, following lysis of thecells in the presence of protease inhibitors, for use in receptorbinding assays. Prostanoid receptor binding assays are performed in 10mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP andIP), containing 1 mM EDTA, 10 mM divalent cation and the appropriateradioligand. The reaction is initiated by addition of membrane protein.Ligands are added in dimethylsulfoxide which is kept constant at 1%(v/v) in all incubations. Non-specific binding is determined in thepresence of 1 μM of the corresponding non-radioactive prostanoid.Incubations are conducted for 60 min at room temperature or 30° C. andterminated by rapid filtration. Specific binding is calculated bysubtracting non specific binding from total binding. The residualspecific binding at each ligand concentration is calculated andexpressed as a function of ligand concentration in order to constructsigmoidal concentration-response curves for determination of ligandaffinity.

Prostanoid Receptor Agonist and Antagonist Assays

Whole cell second messenger assays measuring stimulation (EP₂, EP₄, DPand IP in HEK 293(ebna) cells) or inhibition (EP₃ in humanerythroleukemia (HEL) cells) of intracellular cAMP accumulation ormobilization of intracellular calcium (EP₁, FP and TP in HEK 293(ebna)cells stably transfected with apo-aequorin) are performed to determinewhether receptor ligands are agonists or antagonists. For cAMP assays,cells are harvested and resuspended in HBSS containing 25 mM HEPES, pH7.4. Incubations contain 100 μM RO-20174 (phosphodiesterase type IVinhibitor, available from Biomol) and, in the case of the EP₃ inhibitionassay only, 15 μM forskolin to stimulate cAMP production. Samples areincubated at 37° C. for 10 min, the reaction is terminated and cAMPlevels are then measured. For calcium mobilization assays, cells arecharged with the co-factors reduced glutathione and coelenterazine,harvested and resuspended in Ham's F12 medium. Calcium mobilization ismeasured by monitoring luminescence provoked by calcium binding to theintracellular photoprotein aequorin. Ligands are added indimethylsulfoxide which is kept constant at 1% (v/v) in all incubations.For agonists, second messenger responses are expressed as a function ofligand concentration and both EC₅₀ values and the maximum response ascompared to a prostanoid standard are calculated. For antagonists, theability of a ligand to inhibit an agonist response is determined bySchild analysis and both K_(B) and slope values are calculated.

Rat Paw Edema Assay

The method is the same as described in Chan et al (J. Pharmacol. Exp.Ther. 274: 1531-1537, 1995).

LPS-Induced Pyrexia in Conscious Rats

The method is the same as described in Chan et al (J. Pharmacol. Exp.Ther. 274: 1531-1537, 1995).

LPS-Induced Pyrexia in Conscious Squirrel Monkeys

The method is the same as described in Chan et al (Eur. J. Pharmacol.327: 221-225, 1997).

Acute Inflammatory Hyperalgesia Induced by Carrageenan in Rats

The method is the same as described in Boyce et al (Neuropharmacology33: 1609-1611, 1994).

Adjuvant-Induced Arthritis in Rats

Female Lewis rats (body weight˜146-170 g) were weighed, ear marked, andassigned to groups (a negative control group in which arthritis was notinduced, a vehicle control group, a positive control group administeredindomethacin at a total daily dose of 1 mg/kg and four groupsadministered with a test compound at total daily doses of 0.10-3.0mg/kg) such that the body weights were equivalent within each group. Sixgroups of 10 rats each were injected into a hind paw with 0.5 mg ofMycobacterium butyricum in 0.1 mL of light mineral oil (adjuvant), and anegative control group of 10 rats was not injected with adjuvant. Bodyweights, contralateral paw volumes (determined by mercury displacementplethysmography) and lateral radiographs (obtained under Ketamine andXylazine anesthesia) were determined before (day −1) and 21 daysfollowing adjuvant injection, and primary paw volumes were determinedbefore (day −1) and on days 4 and 21 following adjuvant injection. Therats were anesthetized with an intramuscular injection of 0.03-0.1 mL ofa combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) forradiographs and injection of adjuvant. The radiographs were made of bothhind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds)and Kodak X-OMAT TL film, and were developed in an automatic processor.Radiographs were evaluated for changes in the soft and hard tissues byan investigator who was blinded to experimental treatment. The followingradiographic changes were graded numerically according to severity:increased soft issue volume (0-4), narrowing or widening of joint spaces(0-5) subchondral erosion (0-3), periosteal reaction (0-4), osteolysis(0-4) subluxation (0-3), and degenerative joint changes (0-3). Specificcriteria were used to establish the numerical grade of severity for eachradiographic change. The maximum possible score per foot was 26. A testcompound at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day,indomethacin at a total daily dose of 1 mg/kg/day, or vehicle (0.5%methocel in sterile water) were administered per os b.i.d. beginningpost injection of adjuvant and continuing for 21 days. The compoundswere prepared weekly, refrigerated in the dark until used, and vortexmixed immediately prior to administration.

What is claimed is:
 1. A method of treating a prostaglandin E mediateddisease which comprises administering to a mammalian patient in need ofsuch treatment or prevention a compound of formula I:

wherein: R is a group Ar as defined hereinafter; R¹ is hydrogen,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, X(CH₂)_(p)Ar, or a methylenedioxy groupattached to two adjacent ring carbon atoms; R² is—(CH₂)_(x)C(O)N(R⁴)S(O)_(y)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)C(O)R⁵,—(CH₂)_(x)C(O)N(R⁴)C(O)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)S(O)_(y)R⁵,—(CH₂)_(x)CO₂R⁴, or tetrazol-5-yl optionally substituted by C₁₋₆alkyl;R³ is X(CH₂)_(p)Ar or X(CH₂)_(p)R⁴ or a group of formula (a):

Ar is a group of formula (b) or (c):

 or Ar is naphthyl, which may be unsubstituted or substituted by one ormore R⁷ or R⁸ groups; A is C═O or (C(R⁴)₂)m; each B is —CH₂—; R⁴ ishydrogen or C₁₋₆alkyl, with the proviso that when R⁷ or R⁹ isX—(CR⁴)_(p)—OR⁴, X is (CH₂)_(p)and p is 0 then R⁴ is not C₁₋₆alkyl; R⁵is hydrogen or C₁₋₁₀alkyl or Ar, both of which may be unsubstituted orsubstituted by one or two Cl, F, Br, hydroxy, XC₁₋₅alkyl, C₁₋₅alkyl,NO₂, tetrazol-5-yl optionally substituted by C₁₋₆alkyl, or R⁵ is N(R⁴)₂;R⁶ is R¹⁰, CO₂R¹¹, CO₂C(R¹⁰)₂O(CO)XR¹¹, PO₃(R¹¹)₂, SO₂NR¹¹R¹⁰, NR¹¹SO₂R¹⁰, CONR¹¹SO₂R¹⁰, SO₃R¹¹, S(O)_(q)R¹¹, S(O)_(q)N(R¹¹)C(O)R¹⁰,S(O)_(q)N(R¹¹)S(O)_(q)R¹⁰, C(O)N(R¹¹)C(O)R¹⁰, N(R¹¹)C(O)R¹⁰, N(R¹¹)₂,N(R¹¹)C(O)NR¹¹, P(O)(OR¹¹)R¹¹, CN, —CO₂(CH₂)_(m)C(O)N(R⁴)₂,C(R¹⁰)₂N(R¹¹)₂, C(O)N(R⁴)₂, OR⁴or tetrazolyl optionally substituted byC1-6 alkyl, with the proviso that when R⁷ or R⁹ is —X—(CH₂)_(p)—R⁶, p is0 and X is (CH₂)_(p) then R⁶ is not S(O)_(q)R¹¹; R⁷ and R⁹ areindependently R¹⁰, OH, C₁₋₈ alkoxy, S(O)_(q)R¹⁰, Br, F, I, Cl, CF₃, NO₂,NHCOR⁴, R¹²CO₂R¹¹, —X—R¹³—Y, —X(CR⁴)_(p)R⁴, S(CH₂)_(p)CO₂H,(CH₂)_(p)X—R¹³ —, X(CH₂)_(p)CONR¹¹ SO₂R¹⁰, (CH₂)_(p)XCONR¹¹SO₂R¹⁰ orX(CH₂)_(p)R⁶ wherein each methylene group within —X(CH₂)_(q)R⁶ may beunsubstituted or substituted by one or two —(CH₂)_(p)Ar groups; R⁸ ishydrogen, R¹⁰, OH, C₁₋₅alkoxy, S(O)_(q)R¹⁰, N(R⁴)₂, Br, F, I, Cl orNHCOR⁴wherein the C₁₋₅ alkoxy may be unsubstituted or substituted by OH,methoxy or halogen; R¹⁰ is hydrogen, Ar, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, all of which may be unsubstituted or substituted by one ormore OH,CH₂OH, N(R⁴)₂ or halogen; or R¹⁰ is N(R⁴)₂; R¹¹ is independentlyhydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₈alkynyl, all of which may beunsubstituted or substituted by one or more OH, N(R⁴)₂, CO₂R¹⁴, halogenor XC₁₋₅alkyl; or R¹¹ is (CH₂)_(p)Ar; R¹² is divalent Ar, C₁₋₁₀alkylene,C₁₋₁₀alkylidene, C₂₋₁₀alkenylene, C₂₋₁₀alkynylene, all of which may beunsubstituted or substituted by one or more of OH, CH₂OH, N(R⁴)₂orhalogen; R¹³ is selected from the group consisting of: (1) a bond, (2)when R¹³ is a linking group, selected from the group consisting ofC₁₋₁₀alkylene, C₁₋₁₀alkenylene, C₁₋₁₀alkylidene, C₁₋₁₀alkynylene, all ofwhich may be linear or branched, or phenylene, all of which may beunsubstituted or substituted by one or more OH, N(R⁴)₂, COOH or halogen,and (3) when R¹³ is a terminal group, selected from the group consistingof C₁₋₁₀alkyl, C₁₋₁₀alkenyl, C₁₋₁₀alkynyl, all of which may be linear orbranched, or phenyl, all of which may be unsubstituted or substituted byone or more OH, N(R⁴)₂, COOH or halogen, with the proviso that when R⁷or R⁹ is —(CH₂)_(p)—X—R¹³, p is 0 and X is O then R¹³ is not a linear orbranched alkyl chain of 1 to 8 carbon atoms; R¹⁴ is hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl or C₂₋₇alkynyl; X is (CH₂)_(p), O, NR⁴ or S(O)_(p); Y is CH₃or X(CH₂)_(p)Ar, with the proviso that when R⁷ or R⁹ is X—R¹³—Y, X is Oand R¹³ is a bond, then Y is not CH₃; q is zero, one or two; p is aninteger from 0 to 6; m is 1, 2 or 3; n is 1 to 4; x is 0 to 4; y is 1 or2; the dotted line signifies the optional presence of a bond such thatit represents a single or double bond.
 2. A method of treating aprostaglandin E mediated disease which comprises administering to amammalian patient in need of such treatment or prevention a compound offormula I:

wherein: R is a group Ar as defined hereinafter; R¹ is hydrogen,hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, X(CH₂)_(p)Ar, or a methylenedioxy groupattached to two adjacent ring carbon atoms; R² is—(CH₂)_(x)C(O)N(R⁴)S(O)_(y)R⁵, —(CH₂)_(x)S(O))_(y)N(R⁴)C(O)R⁵,—(CH₂)_(x)C(O)N(R⁴)C(O)R⁵, —(CH₂)_(x)S(O)_(y)N(R⁴)S(O)_(y)R⁵,—(CH₂)_(x)CO₂R⁴, or tetrazol-5-yl optionally substituted by C₁₋₆alkyl;R³ is X(CH₂)_(p)Ar or X(CH₂)_(p)R⁴or a group of formula (a):

Ar is a group of formula (b) or (C):

 or Ar is naphthyl, which may be unsubstituted or substituted by one ormore R⁷ or R⁸ groups; A is C═O or (C(R⁴)₂)m; each B is —CH₂—; R⁴ ishydrogen or C₁₋₆alkyl, with the proviso that when R⁷ or R⁹ isX—(CR⁴)_(p)—OR⁴, X is (CH₂)_(p) and p is 0 then R⁴is not C₁₋₆alkyl; R⁵is hydrogen or C₁₋₆alkyl or Ar, both of which may be unsubstituted orsubstituted by one or two Cl, F, Br, hydroxy, XC₁₋₅alkyl, C₁₋₅alkyl,NO₂, tetrazol-5-yl optionally substituted by C₁₋₆alkyl, or R⁵ is N(R⁴)₂;R⁶ is R¹⁰, CO₂R¹¹, CO₂C(R¹⁰)₂O(CO)XR¹¹, PO₃(R¹¹)₂, SO₂NR¹¹R¹⁰,NR¹¹SO₂R¹⁰, CONR¹¹ SO₂R¹⁰, SO₃R¹¹, S(O)_(q)R¹¹, S(O)_(q)N(R¹¹)C(O)R¹⁰,S(O)_(q)N(R¹¹)S(O)_(q)R¹⁰, C(O)N(R¹¹)C(O)R¹⁰, N(R¹¹)C(O)R¹⁰, N(R¹¹)₂,N(R¹¹)C(O)NR¹¹, P(O)(OR¹¹)R¹¹, CN, —CO₂(CH₂)_(m)C(O)N(R⁴)₂,C(R¹⁰O)₂N(R¹¹)₂, C(O)N(R⁴)₂, OR⁴or tetrazolyl optionally substituted byC1-6 alkyl, with the proviso that when R⁷ or R⁹ is —X—(CH₂)_(p)—R⁶, p is0 and X is (CH₂)_(p) then R⁶ is not S(O)_(q)R¹¹; R⁷ and R⁹ areindependently R¹⁰, OH, C₁₋₈alkoxy, S(O)_(q)R¹⁰, Br, F, I, Cl, CF₃, NO₂,NHCOR⁴, R¹²CO₂R¹¹, —X—R¹³—Y, —X(CR⁴)_(p)OR⁴, S(CH₂)_(p)CO₂H,(CH₂)_(p)X—R¹³, —X(CH₂)_(p)CONR¹¹SO₂R¹⁰, (CH₂)_(p)XCONR¹¹SO₂R¹⁰orX(CH₂)_(p)R⁶ wherein each methylene group within —X(CH₂)_(q)R⁶ may beunsubstituted or substituted by one or two —(CH₂)_(p)Ar groups; R⁸ ishydrogen, R¹⁰, OH, C₁₋₅alkoxy, S(O)_(q)R¹⁰, N(R⁴)₂, Br, F, I, Cl orNHCOR⁴ wherein the C₁₋₅alkoxy may be unsubstituted or substituted by OH,methoxy or halogen; R¹⁰ is hydrogen, Ar, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, all of which may be unsubstituted or substituted by one ormore OH,CH₂OH, N(R⁴)₂or halogen; or R¹⁰ is N(R⁴)₂; R¹¹ is independentlyhydrogen, C₁₋₁₀alkyl, C₂₋₁₀alkenyl or C₂₋₈alkynyl, all of which may beunsubstituted or substituted by one or more OH, N(R⁴)₂, CO₂R¹⁴, halogenor XC₁₋₅alkyl; or R¹¹ is (CH₂)_(p)Ar; R¹² is divalent Ar, C₁₋₁₀alkylene,C₁₋₁₀alkylidene, C₂₋₁₀alkenylene, C₂₋₁₀alkynylene, all of which may beunsubstituted or substituted by one or more of OH, CH₂OH, N(R⁴)₂orhalogen; R¹³ is selected from the group consisting of: (1) a bond, (2)R¹³ is a linking group, selected from the group consisting ofC₁₋₁₀alkylene, C₁₋₁₀alkylene, C₁₋₁₀alkylidene, C₁₋₁₀alkynylene, all ofwhich may be linear or branched, or phenylene, all of which may beunsubstituted of substituted by one or more OH, N(R⁴)₂, COOH or halogen,and (3) when R¹³ is a terminal group, selected from the group consistingof C₁₋₁₀alkyl, C₁₋₁₀alkylenyl, C₁₋₁₀alkynyl, all of which may be linearor branched, or phenyl, all of which may be unsubstituted or substitutedby one or more OH, N(R⁴)₂, COOH or halogen, with the proviso that whenR⁷ or R⁹ is —(CH₂)₂—X—R¹³, p is 0 and X is O then R¹³ is not a linear orbranched alkyl chain of 1 to 8 carbon atoms; R¹⁴ is hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl , C₂₋₇alkynyl; X is (CH₂)_(p), O, NR⁴ or S(O)_(p); Y is(CH₃) or X(CH₂)_(p)Ar, with the proviso that when R⁷ or R⁹ is X—R¹³—Y, Xis O and R¹³ is a bond, then Y is not CH₃; q is zero, one or two; p isan integer from 0 to 6; m is 1, 2 or 3; n is 1 to 4; x is 0 to 4; y is 1to 2; the dotted line signifies the optional presence of a bond suchthat it represents a single or double bond, wherein the prostaglandinmediated disease is selected from the group consisting of: (1) pain,fever or inflammation associated with rheumatic fever, influenza orother viral infections, common cold, low back and neck pain, skeletalpain, post-partum pain, dysmenorrhea, headache, migraine, toothache,sprains and strains, myositis, neuralgia, synovitis, arthritis,including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, bursitis, burnsincluding radiation and corrosive chemical injuries, sunburns, painfollowing surgical and dental procedures as well as immune andautoimmune diseases; and (2) thrombosis.
 3. A method according to claim2 wherein the prostaglandin mediated disease is selected from the groupconsisting of: pain, fever or inflammation associated with rheumaticfever, influenza or other viral infections, common cold, low back andneck pain, skeletal pain, post-partum pain, dysmenorrhea, headache,migraine, toothache, sprains and strains, myositis, neuralgia,synovitis, arthritis, including rheumatoid arthritis, degenerative jointdiseases (osteoarthritis), gout and ankylosing spondylitis, bursitis,burns including radiation and corrosive chemical injuries, sunburns,pain following surgical and dental procedures as well as immune andautoimmune diseases.
 4. A method according to claim 3 wherein theprostaglandin mediated disease is pain, fever or inflammation associatedwith dysmenorrhea.
 5. A compound selected from one of the followingtables: TABLE 1

R¹ R² R³ X Y(R^(7,8)) Z(R^(7,8)) A Cpd 2-(2,6-Cl₂- H H benzene 1,3benzene 1,2 benzene CH₂—CH₂ 1 benzyloxy) diyl diyl diyl 2-Benzyl H Hbenzene 1,3 benzene 1,2 benzene CH₂—CH(CH₃) 2 oxy diyl diyl diyl2-Benzyl H H benzene 1,3 benzene 1,2 benzene CH═CH 7 oxy diyl diyl diylH H H naphthyl 1,3 benzene 1,2 benzene CH₂—CH₂ 11 diyl diyl H H H phenyl1,3 benzene 1,2 benzene CH₂—CH₂ 12 diyl diyl 2-Benzyl H H benzene 1,3benzene 1,2 benzene CH₂—CH₂—CH₂ 13 oxy diyl diyl diyl 2-Chloro 3-Cl Hbenzene 1,3 benzene 1,2 benzene CH₂—CH₂ 14 triyl diyl diyl 2-Phenoxy H Hbenzene 1,3 benzene 1,2 benzene CH₂—CH₂ 16 methyl diyl diyl diyl4-Benzyl H H benzene 1,3 benzene 1,2 benzene CH₂—CH₂ 17 oxy diyl diyldiyl 4-Benzyl H H 1-naphtha 1,3 benzene 1,2 benzene CH₂—CH₂ 18 oxylenediyl diyl diyl 2-Benzyl H H benzene 1,3 benzene 1,2 benzene CH₂—CH₂21 oxy diyl diyl diyl 2-Benzyl H H benzene 2,6-pyridine 1,2 benzeneCH═CH 38 oxy diyl diyl diyl 2-Benzyl H H benzene 1,3-benzene 1,2 benzeneCH═CH 41 oxy diyl triyl (5-Cl) triyl (4-F) 2-Benzyl H H benzene1,3-benzene 1,2 benzene CH═C(CH₃) 42 oxy diyl triyl (5-OCF₃) triyl(4-Cl) 2-Benzyl H H benzene 1,3-benzene 1,2 benzene CH₂—CH₂ 43 oxy diyltriyl (5-CN) triyl (5-Cl) 2-Benzyl H H benzene 1,3-benzene 1,2 benzeneCH═CH 44 oxy diyl triyl (5-Me) triyl (5-OMe) 2-Benzyl H H benzene1,3-benzene 1,2 benzene CH═C(CH₃) 45 oxy diyl triyl (2-Me) triyl (6-Cl)2-Benzyl H H benzene 1,3-benzene 1,2 benzene CH₂—CH₂ 46 oxy diyl triyl(2-OMe) triyl (6-OMe)

TABLE 2

R², R³ = H, Z = 1,2-benzenediyl R¹ X Y A R⁵ Cpd 2-Benzyloxy benzene 1,3benzene CH═CH 2-thienyl 53 diyl diyl 2-Benzyloxy benzene 1,3-benzeneCH₂—C(CH₃)₂ styryl 54 diyl diyl 2-(4-MeO- benzene 3,5-thiopheneCH₂—CH(CH₃) benzyl 55 benzyloxy) diyl diyl 2-(2,3-Cl₂- benzene1,3-benzene CH═CH cyclohexyl 56 benzyloxy) diyl diyl 2-(4-CF₃- benzene1,3-benzene CH₂—CH(CH₃) 4-Cl-phenyl 58 benzyloxy) diyl diyl 2-(4-MeO-benzene 1,3-benzene CH₂—C(CH₃)₂ 4-(CH₃SO₂)phenyl 60 benzyloxy) diyl diyl2-Benzyloxy benzene 1,3-benzene CH═CH 2-MeO-5-Br-phenyl 62 diyl diyl2-(2,3-Cl₂- benzene 1,3-benzene CH₂—CH(CH₃) 3,4-Cl₂-phenyl 64 benzyloxy)diyl diyl 2-(4-CF₃- benzene 1,3-benzene CH₂—C(CH₃)₂ 3-Cl-4-F-phenyl 66benzyloxy) diyl diyl 2-(4-MeO- benzene 1,3-benzene CH═CH 1-imidazoyl 68benzyloxy) diyl diyl 2-Benzyloxy benzene 1,3-benzene CH₂—CH(CH₃)3-indolyl 70 diyl diyl

TABLE 3

R3 = H, R¹ R² X Y(R^(7,8)) A B Cpd 3-(2-Ph—Et—SCH₂) H benzene 1,2benzene CH₂—CH₂ 2-thienyl 72 diyl diyl 4-(2-Ph—Et—SCH₂) H benzene 1,2benzene CH₂—CH₂ 2-thienyl 73 diyl diyl 4-(2-Ph—Et—SCH₂) H benzene 1,2benzene CH₂—CH₂—CH₂ 2-thienyl 74 diyl diyl 4-(3(-3-(2-Ph—Et— H benzene1,2 benzene CH₂—CH₂ 2-thienyl 75 SCH₂)Ph-oxy)Pr- diyl diyl oxy)4-(3(-3-(2-Ph—Et— H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 76S(O)—CH₂)Ph- diyl diyl oxy)Pr-oxy) 4-(3-(3-Me—Ph- H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 77 oxy)Pr-oxy) diyl diyl 4-(3(-3-(2-Ph—Et- H benzene1,2 benzene CH₂—CH₂ 2-thienyl 78 S(O)₂—CH₂)Ph- diyl diyl oxy)Pr-oxy)4-Carbazole-yl- H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 79 CH₂ diyl diyl4-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 80 diyl triyl(5-Bn) 4-(3-(3-Me—Ph- H benzene 1,2 benzene CH₂—CH(CH₃) 2-thienyl 81oxy)Pr-oxy) diyl diyl 4-(3-(3-(3-Ph)Pr- H benzene 1,2 benzene CH₂—CH₂2-thienyl 82 oxy CH₂)Ph- diyl diyl oxy)Pr-oxy) 4-(3-(2- H benzene 1,2benzene CH₂—CH₂ 2-thienyl 83 (Qn)ethenyl) diyl diyl Ph-oxy)Pr-oxy)4-(3-(3-2-((4-Cl— H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 84Ph)—Et)Ph-oxy)Pr- diyl diyl oxy) 4-(3-(3-(4-Ph—Ph- H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 85 oxy-CH₂)Ph- diyl diyl oxy)Pr-oxy) 3-(3-(3-Me—Ph- Hbenzene 1,2 benzene CH₂—CH₂ 2-thienyl 86 oxy)Pr-oxy) diyl diyl4-(2-(3-Tolyl) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 87 acetoxy CH₂)diyl diyl 4-(2-(3-Tolyl) H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 88acetamide CH₂) diyl diyl 3-(3-(2-(Qn)CH₂ H benzene 1,2 benzene CH₂—CH₂2-thienyl 89 oxy) diyl diyl 3-Thiomethyl H benzene 1,2 benzene CH₂—CH₂2-thienyl 90 diyl diyl 3-Methylsulfone H benzene 1,2 benzene CH₂—CH₂2-thienyl 91 diyl diyl 4-(3-(3-Me—Ph- 3,5-Br benzene 1,2 benzene CH₂—CH₂2-thienyl 92 oxy)Pr-oxy) tetrayl diyl 3-(3-(2-(Qn) H benzene 1,2 benzeneCH₂—CH₂ 2-thienyl 93 ethenyl)Ph- diyl diyl oxy)Pr-oxy) 3-(2-(Qn)ethenyl)H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 94 diyl diyl 3-(3-(3-Me—Ph- Hbenzene 1,2 benzene CH₂— 2-thienyl 95 oxy)Pr-oxy) diyl diyl CH((CH₂)₃Ph)3-(2-Ph-2-oxy- H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 96 ethoxy) diyldiyl 3-(2-(3-Phenyl-Pr- H benzene 1,2 benzene CH₂—CH₂ 2-thienyl 97oxy)2-Ph-ethoxy) diyl diyl 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH2-thienyl 98 diyl diyl 4-Chloro 3-Cl benzene 1,2 benzene CH═CH 2-thienyl99 triyl diyl 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 2-thienyl100 diyl triyl (5-CF₃) 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH2-MeO-5-Br- 101 oxy)Pr-oxy) diyl triyl (5-OMe) phenyl 4-Chloro 3-Clbenzene 1,2 benzene CH═CH 3-Cl-4-F- 102 triyl triyl (5-Me) phenyl3-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH═CH 2-thienyl 103 diyl triyl(5-Bn) 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 2-MeO-5-Br— 104diyl triyl (6-Cl) Ph 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH3-Cl-4-F- 105 oxy)Pr-oxy) diyl triyl (6-OMe) phenyl 4-Chloro 3-Clbenzene 1,2 benzene CH═CH 2-thienyl 106 triyl triyl (3-Cl)3-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH═CH 2-MeO-5-Br— 107 diyl triyl(3-OMe) Ph 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 3-Cl-4-F- 108diyl triyl (4-F) phenyl 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH2-thienyl 109 oxy)Pr-oxy) diyl triyl (4-Cl) 4-Chloro 3-Cl benzene 1,2benzene CH═CH 4-MeO- 110 triyl diyl phenyl 3-Ph—Et—SCH₂ H benzene 1,2benzene CH═CH 4-CF₃-phenyl 111 diyl diyl 3-(2-(Qn)ethenyl) H benzene 1,2benzene CH═CH 4-(CH₃SO₂) 112 diyl diyl phenyl 3-(3-(3-Me—Ph- H benzene1,2 benzene CH═CH 2-methyl 113 oxy)Pr-oxy) diyl diyl phenyl 4-Chloro3-Cl benzene 1,2 benzene CH═CH 2,3-Cl₂- 114 triyl diyl phenyl3-(2-Ph—Et—SCH₂) H benzene 1,2 benzene CH═CH 2-NO₂-4-Cl- 115 diyl diylphenyl 3-(2-(Qn)ethenyl) H benzene 1,2 benzene CH═CH 2,5-(CH₃)₂- 116diyl diyl phenyl 3-(3-(3-Me—Ph- H benzene 1,2 benzene CH═CH 2,6-F₂- 117oxy)Pr-oxy) diyl diyl phenyl 4-Chloro H benzene 1,2 benzene CH═CH3,4-Cl₂- 118 diyl diyl phenyl 3-(2-Ph—Et—SCH₂) H benzene 1,2 benzeneCH═CH 3,5-Br₂- 119 diyl diyl phenyl 3-(2-(Qn)ethenyl) H benzene 1,2benzene CH═CH 2-thiazoyl 120 diyl diyl

or pharmaceutically acceptable salt thereof, wherein Qn represents7-chloro-quinol-2-yl, 2-Ph-Et-SCH₂ represents 2-phenylethylthiomethyl,and 3-(3-Me-Ph-oxy)Pr-oxy represents 3-(3-methylphenoxy)propyl-1-oxy.